@article{mei_li_wang_zhu_huang_hu_popowski_cheng_2023, title={An inhaled bioadhesive hydrogel to shield non-human primates from SARS-CoV-2 infection}, volume={2}, ISSN={1476-1122 1476-4660}, url={http://dx.doi.org/10.1038/s41563-023-01475-7}, DOI={10.1038/s41563-023-01475-7}, abstractNote={The surge of fast-spreading SARS-CoV-2 mutated variants highlights the need for fast, broad-spectrum strategies to counteract viral infections. In this work, we report a physical barrier against SARS-CoV-2 infection based on an inhalable bioadhesive hydrogel, named spherical hydrogel inhalation for enhanced lung defence (SHIELD). Conveniently delivered via a dry powder inhaler, SHIELD particles form a dense hydrogel network that coats the airway, enhancing the diffusional barrier properties and restricting virus penetration. SHIELD's protective effect is first demonstrated in mice against two SARS-CoV-2 pseudo-viruses with different mutated spike proteins. Strikingly, in African green monkeys, a single SHIELD inhalation provides protection for up to 8 hours, efficiently reducing infection by the SARS-CoV-2 WA1 and B.1.617.2 (Delta) variants. Notably, SHIELD is made with food-grade materials and does not affect normal respiratory functions. This approach could offer additional protection to the population against SARS-CoV-2 and other respiratory pathogens.}, journal={Nature Materials}, publisher={Springer Science and Business Media LLC}, author={Mei, Xuan and Li, Junlang and Wang, Zhenzhen and Zhu, Dashuai and Huang, Ke and Hu, Shiqi and Popowski, Kristen D. and Cheng, Ke}, year={2023}, month={Feb} }
 @article{zhu_liu_huang_li_mei_li_cheng_2023, title={Intrapericardial long non-coding RNA–<i>Tcf21</i> antisense RNA inducing demethylation administration promotes cardiac repair}, volume={44}, ISSN={0195-668X 1522-9645}, url={http://dx.doi.org/10.1093/eurheartj/ehad114}, DOI={10.1093/eurheartj/ehad114}, abstractNote={Epicardium and epicardium-derived cells are critical players in myocardial fibrosis. Mesenchymal stem cell-derived extracellular vesicles (EVs) have been studied for cardiac repair to improve cardiac remodelling, but the actual mechanisms remain elusive. The aim of this study is to investigate the mechanisms of EV therapy for improving cardiac remodelling and develop a promising treatment addressing myocardial fibrosis.Extracellular vesicles were intrapericardially injected for mice myocardial infarction treatment. RNA-seq, in vitro gain- and loss-of-function experiments, and in vivo studies were performed to identify targets that can be used for myocardial fibrosis treatment. Afterward, a lipid nanoparticle-based long non-coding RNA (lncRNA) therapy was prepared for mouse and porcine models of myocardial infarction treatment. Intrapericardial injection of EVs improved adverse myocardial remodelling in mouse models of myocardial infarction. Mechanistically, Tcf21 was identified as a potential target to improve cardiac remodelling. Loss of Tcf21 function in epicardium-derived cells caused increased myofibroblast differentiation, whereas forced Tcf21 overexpression suppressed transforming growth factor-β signalling and myofibroblast differentiation. LncRNA-Tcf21 antisense RNA inducing demethylation (TARID) that enriched in EVs was identified to up-regulate Tcf21 expression. Formulated lncRNA-TARID-laden lipid nanoparticles up-regulated Tcf21 expression in epicardium-derived cells and improved cardiac function and histology in mouse and porcine models of myocardial infarction.This study identified Tcf21 as a critical target for improving cardiac fibrosis. Up-regulating Tcf21 by using lncRNA-TARID-laden lipid nanoparticles could be a promising way to treat myocardial fibrosis. This study established novel mechanisms underlying EV therapy for improving adverse remodelling and proposed a lncRNA therapy for cardiac fibrosis.}, number={19}, journal={European Heart Journal}, publisher={Oxford University Press (OUP)}, author={Zhu, Dashuai and Liu, Shuo and Huang, Ke and Li, Junlang and Mei, Xuan and Li, Zhenhua and Cheng, Ke}, year={2023}, month={Mar}, pages={1748–1760} }
 @article{fan_li_shen_wang_liu_zhu_wang_li_popowski_ou_et al._2022, title={Decoy Exosomes Offer Protection Against Chemotherapy-Induced Toxicity}, volume={9}, ISSN={["2198-3844"]}, DOI={10.1002/advs.202203505}, abstractNote={Cancer patients often face severe organ toxicity caused by chemotherapy. Among these, chemotherapy-induced hepatotoxicity and cardiotoxicity are the main causes of death of cancer patients. Chemotherapy-induced cardiotoxicity even creates a new discipline termed "cardio-oncology". Therefore, relieving toxicities induced by chemotherapy has become a key issue for improving the survival and quality of life in cancer patients. In this work, mesenchymal stem cell exosomes with the "G-C" abundant tetrahedral DNA nanostructure (TDN) are modified to form a decoy exosome (Exo-TDN). Exo-TDN reduces DOX-induced hepatotoxicity as the "G-C" base pairs scavenge DOX. Furthermore, Exo-TDN with cardiomyopathic peptide (Exo-TDN-PCM) is engineered for specific targeting to cardiomyocytes. Injection of Exo-TDN-PCM significantly reduces DOX-induced cardiotoxicity. Interestingly, Exo-TDN-PCM can also promote macrophage polarization into the M2 type for tissue repair. In addition, those decoy exosomes do not affect the anticancer effects of DOX. This decoy exosome strategy serves as a promising therapy to reduce chemo-induced toxicity.}, journal={ADVANCED SCIENCE}, author={Fan, Miao and Li, Hang and Shen, Deliang and Wang, Zhaoshuo and Liu, Huifang and Zhu, Dashuai and Wang, Zhenzhen and Li, Lanya and Popowski, Kristen D. and Ou, Caiwen and et al.}, year={2022}, month={Sep} }
 @article{hu_zhu_li_cheng_2022, title={Detachable Microneedle Patches Deliver Mesenchymal Stromal Cell Factor-Loaded Nanoparticles for Cardiac Repair}, volume={9}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.2c03060}, abstractNote={Intramyocardial injection is a direct and efficient approach to deliver therapeutics to the heart. However, the injected volume must be very limited, and there is injury to the injection site and leakage issues during heart beating. Herein, we developed a detachable therapeutic microneedle (MN) patch, which is comprised of mesenchymal stromal cell-secreted factors (MSCF)-loaded poly(lactic-co-glycolic acid) nanoparticles (NP) in MN tips made of elastin-like polypeptide gel, with a resolvable non-cross-linked hyaluronic acid (HA) gel as the MN base. The tips can be firmly inserted into the infarcted myocardium after base removal, and no suture is needed. In isolated neonatal rat cardiac cells, we found that the cellular uptake of MSCF-NP in the cardiomyocytes was higher than in cardiac fibroblasts. MSCF-NP promoted the proliferation of injured cardiomyocytes. In a rat model of myocardial infarction, MN-MSCF-NP treatment reduced cardiomyocyte apoptosis, restored myocardium volume, and reduced fibrosis during the cardiac remodeling process. Our work demonstrated the therapeutic potential of MN to deliver MSCF directly into the myocardium and provides a promising treatment approach for cardiac diseases.}, journal={ACS NANO}, author={Hu, Shiqi and Zhu, Dashuai and Li, Zhenhua and Cheng, Ke}, year={2022}, month={Sep} }
 @article{fang_li_zhong_zhou_lee_cheng_li_2022, title={Engineering stem cell therapeutics for cardiac repair}, volume={171}, ISSN={["1095-8584"]}, DOI={10.1016/j.yjmcc.2022.06.013}, abstractNote={Cardiovascular disease is the leading cause of death in the world. Stem cell-based therapies have been widely investigated for cardiac regeneration in patients with heart failure or myocardial infarction (MI) and surged ahead on multiple fronts over the past two decades. To enhance cellular therapy for cardiac regeneration, numerous engineering techniques have been explored to engineer cells, develop novel scaffolds, make constructs, and deliver cells or their derivatives. This review summarizes the state-of-art stem cell-based therapeutics for cardiac regeneration and discusses the emerged bioengineering approaches toward the enhancement of therapeutic efficacy of stem cell therapies in cardiac repair. We cover the topics in stem cell source and engineering, followed by stem cell-based therapies such as cell aggregates and cell sheets, and biomaterial-mediated stem cell therapies such as stem cell delivery with injectable hydrogel, three-dimensional scaffolds, and microneedle patches. Finally, we discuss future directions and challenges of engineering stem cell therapies for clinical translation.}, journal={JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY}, author={Fang, Jun and Li, Jennifer J. and Zhong, Xintong and Zhou, Yue and Lee, Randall J. and Cheng, Ke and Li, Song}, year={2022}, month={Oct}, pages={56–68} }
 @article{wang_popowski_zhu_abad_wang_liu_lutz_de naeyer_demarco_denny_et al._2022, title={Exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain as an inhalable COVID-19 vaccine}, volume={7}, ISSN={["2157-846X"]}, url={https://doi.org/10.1038/s41551-022-00902-5}, DOI={10.1038/s41551-022-00902-5}, abstractNote={The first two mRNA vaccines against infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that were approved by regulators require a cold chain and were designed to elicit systemic immunity via intramuscular injection. Here we report the design and preclinical testing of an inhalable virus-like-particle as a COVID-19 vaccine that, after lyophilisation, is stable at room temperature for over three months. The vaccine consists of a recombinant SARS-CoV-2 receptor-binding domain (RBD) conjugated to lung-derived exosomes which, with respect to liposomes, enhance the retention of the RBD in both the mucus-lined respiratory airway and in lung parenchyma. In mice, the vaccine elicited RBD-specific IgG antibodies, mucosal IgA responses and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile in the animals’ lungs, and cleared them of SARS-CoV-2 pseudovirus after a challenge. In hamsters, two doses of the vaccine attenuated severe pneumonia and reduced inflammatory infiltrates after a challenge with live SARS-CoV-2. Inhalable and room-temperature-stable virus-like particles may become promising vaccine candidates.}, journal={NATURE BIOMEDICAL ENGINEERING}, author={Wang, Zhenzhen and Popowski, Kristen D. and Zhu, Dashuai and Abad, Blanca Lopez de Juan and Wang, Xianyun and Liu, Mengrui and Lutz, Halle and De Naeyer, Nicole and DeMarco, C. Todd and Denny, Thomas N. and et al.}, year={2022}, month={Jul} }
 @article{shi_cheng_cheng_2022, title={Gecko-Inspired Adhesives with Asymmetrically Tilting-Oriented Micropillars}, volume={38}, ISSN={["0743-7463"]}, DOI={10.1021/acs.langmuir.2c01002}, abstractNote={The anisotropic adhesion behavior of the gecko is closely related to their feet and is comprised of keratinous hairs, setae, where van der Waals forces permit attachment and detachment during locomotion. Previous research either achieved only isotropic adhesion behaviors or involved the complicated photolithography method. Here, we reported a simple way to achieve the anisotropic adhesion behaviors of gecko-inspired adhesives, consisting of micropillars with asymmetrically tilted orientation via the 3D printing technique. The adhesive forces of structured polymer pillars achieved 4-fold stronger, compared to controls with the plain surface. The anisotropic adhesion behavior is presented on the patterned surface and is two times stronger along the gripping direction compared to the releasing direction on the adhesives, which is attributed to the asymmetric stress distributions at the edges, as well as the stresses resulting from the moment with the sheared top. The finite element analysis is applied to demonstrate the stress distributions and displacement variations. This work provides the insight into the design and fabrication of gecko-inspired adhesives with anisotropic adhesion behaviors in practical applications.}, number={29}, journal={LANGMUIR}, author={Shi, Weiwei and Cheng, Xiao and Cheng, Ke}, year={2022}, month={Jul} }
 @article{popowski_moatti_scull_silkstone_lutz_lópez de juan abad_george_belcher_zhu_mei_et al._2022, title={Inhalable dry powder mRNA vaccines based on extracellular vesicles}, volume={5}, ISSN={2590-2385}, url={http://dx.doi.org/10.1016/j.matt.2022.06.012}, DOI={10.1016/j.matt.2022.06.012}, abstractNote={Respiratory diseases are a global burden, with millions of deaths attributed to pulmonary illnesses and dysfunctions. Therapeutics have been developed, but they present major limitations regarding pulmonary bioavailability and product stability. To circumvent such limitations, we developed room-temperature-stable inhalable lung-derived extracellular vesicles or exosomes (Lung-Exos) as mRNA and protein drug carriers. Compared with standard synthetic nanoparticle liposomes (Lipos), Lung-Exos exhibited superior distribution to the bronchioles and parenchyma and are deliverable to the lungs of rodents and nonhuman primates (NHPs) by dry powder inhalation. In a vaccine application, severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein encoding mRNA-loaded Lung-Exos (S-Exos) elicited greater immunoglobulin G (IgG) and secretory IgA (SIgA) responses than its loaded liposome (S-Lipo) counterpart. Importantly, S-Exos remained functional at room-temperature storage for one month. Our results suggest that extracellular vesicles can serve as an inhaled mRNA drug-delivery system that is superior to synthetic liposomes.}, number={9}, journal={Matter}, publisher={Elsevier BV}, author={Popowski, Kristen D. and Moatti, Adele and Scull, Grant and Silkstone, Dylan and Lutz, Halle and López de Juan Abad, Blanca and George, Arianna and Belcher, Elizabeth and Zhu, Dashuai and Mei, Xuan and et al.}, year={2022}, month={Sep}, pages={2960–2974} }
 @article{zhu_liu_huang_wang_hu_li_li_cheng_2022, title={Intrapericardial Exosome Therapy Dampens Cardiac Injury via Activating Foxo3}, volume={131}, ISSN={["1524-4571"]}, url={https://doi.org/10.1161/CIRCRESAHA.122.321384}, DOI={10.1161/CIRCRESAHA.122.321384}, abstractNote={Background: Mesenchymal stem cell (MSC)-derived exosomes are well recognized immunomodulating agents for cardiac repair, while the detailed mechanisms remain elusive. The Pericardial drainage pathway provides the heart with immunosurveillance and establishes a simplified model for studying the mechanisms underlying the immunomodulating effects of therapeutic exosomes. Methods: Myocardial infarction (MI) models with and without pericardiectomy (corresponding to Tomy MI and NonTomy MI) were established to study the functions of pericardial drainage pathway in immune activation of cardiac-draining mediastinal lymph node (MLN). Using the NonTomy MI model, MSC exosomes or vehicle PBS was intrapericardially injected for MI treatment. Via cell sorting and RNA-seq (RNA-sequencing) analysis, the differentially expressed genes were acquired for integrated pathway analysis to identify responsible mechanisms. Further, through functional knockdown/inhibition studies, application of cytokines and neutralizing antibodies, western blot, flow cytometry, and cytokine array, the molecular mechanisms were studied. In addition, the therapeutic efficacy of intrapericardially injected exosomes for MI treatment was evaluated through functional and histological analyses. Results: We show that the pericardial draining pathway promoted immune activation in the MLN following MI. Intrapericardially injected exosomes accumulated in the MLN and induced regulatory T cell differentiation to promote cardiac repair. Mechanistically, uptake of exosomes by major histocompatibility complex (MHC)-II + antigen-presenting cells (APCs) induced Foxo3 activation via the protein phosphatase (PP)-2A/p-Akt/forkhead box O3 (Foxo3) pathway. Foxo3 dominated APC cytokines (IL-10, IL-33, and IL-34) expression and built up a regulatory T cell (Treg)-inducing niche in the MLN. The differentiation of Tregs as well as their cardiac deployment were elevated, which contributed to cardiac inflammation resolution and cardiac repair. Conclusions: This study reveals a novel mechanism underlying the immunomodulation effects of MSC exosomes and provides a promising candidate (PP2A/p-Akt/Foxo3 signaling pathway) with a favorable delivery route (intrapericardial injection) for cardiac repair.}, number={10}, journal={CIRCULATION RESEARCH}, author={Zhu, Dashuai and Liu, Shuo and Huang, Ke and Wang, Zhenzhen and Hu, Shiqi and Li, Junlang and Li, Zhenhua and Cheng, Ke}, year={2022}, month={Oct}, pages={E135–E150} }
 @article{li_lv_zhu_mei_huang_wang_li_zhang_hu_popowski_et al._2022, title={Intrapericardial hydrogel injection generates high cell retention and augments therapeutic effects of mesenchymal stem cells in myocardial infarction}, volume={427}, ISSN={["1873-3212"]}, url={https://doi.org/10.1016/j.cej.2021.131581}, DOI={10.1016/j.cej.2021.131581}, abstractNote={Although cell therapy has shown potential efficacy in the treatment of heart diseases, one challenge is low cellular retention rate and poor engraftment. We sought to perform a head-to-head comparison on cell retention and therapeutic benefits of intramyocardial (IM) injection and intrapericardial cavity (IPC) injection of adult stem cells in hydrogel. Mouse green fluorescent protein (GFP)-labeled mesenchymal stem cells (MSCs) were combined in extracellular matrix (ECM) hydrogel and injected into the pericardial cavity or the myocardium of the heart of C57BL/6 mice that had been subjected to a myocardial infarction. The IPC injection, as an alternative cell delivery route, led to better cardiac function in our mouse model with myocardial infarction, which was showed by echocardiographies in the short term (2 weeks) and the long term (6 weeks). This result was attributed to 10-fold higher engraftment of MSCs injected via IPC route (42.5 ± 7.4%) than that of MSCs injected intramyocardially (4.4 ± 1.3%). Immunohistochemistry data revealed better cellular proliferation, less apoptosis, and better vascular regeneration in the myocardium after IPC delivery of MSCs. CD63-RFP exosome labeling system showed that heart cells including cardiomyocytes absorbed MSC-exosomes at higher rates when MSCs were injected via IPC route, compared to the results from IM injections, indicating more extensive paracrine activity of MSCs after IPC injections. What is more, the feasibility and safety of IPC injection were demonstrated in a porcine model with minimally invasive procedure. Intrapericardial cavity injection gave a promising solution for the low retention issue of MSCs in the infarcted heart.}, journal={CHEMICAL ENGINEERING JOURNAL}, publisher={Elsevier BV}, author={Li, Junlang and Lv, Yongbo and Zhu, Dashuai and Mei, Xuan and Huang, Ke and Wang, Xianyun and Li, Zhenhua and Zhang, Sichen and Hu, Shiqi and Popowski, Kristen D. and et al.}, year={2022}, month={Jan} }
 @article{zhang_zhang_zhu_li_wang_li_mei_xu_cheng_zhong_2022, title={Nanoparticles functionalized with stem cell secretome and CXCR4-overexpressing endothelial membrane for targeted osteoporosis therapy}, volume={20}, ISSN={["1477-3155"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85122993345&partnerID=MN8TOARS}, DOI={10.1186/s12951-021-01231-6}, abstractNote={Osteoporosis is a chronic condition affecting patients' morbidity and mortality and represents a big socioeconomic burden. Because stem cells can proliferate and differentiate into bone-forming cells, stem cell therapy for osteoporosis has been widely studied. However, cells as a live drug face multiple challenges because of their instability during preservation and transportation. In addition, cell therapy has potential adverse effects such as embolism, tumorigenicity, and immunogenicity.Herein, we sought to use cell-mimicking and targeted therapeutic nanoparticles to replace stem cells. We fabricated nanoparticles (NPs) using polylactic-co-glycolic acid (PLGA) loaded with the secretome (Sec) from mesenchymal stem cells (MSCs) to form MSC-Sec NPs. Furthermore, we cloaked the nanoparticles with the membranes from C-X-C chemokine receptor type 4 (CXCR4)-expressing human microvascular endothelial cells (HMECs) to generate MSC-Sec/CXCR4 NP. CXCR4 can target the nanoparticles to the bone microenvironment under osteoporosis based on the CXCR4/SDF-1 axis.In a rat model of osteoporosis, MSC-Sec/CXCR4 NP were found to accumulate in bone, and such treatment inhibited osteoclast differentiation while promoting osteogenic proliferation. In addition, our results showed that MSC-Sec/CXCR4 NPs reduce OVX-induced bone mass attenuation in OVX rats.}, number={1}, journal={JOURNAL OF NANOBIOTECHNOLOGY}, author={Zhang, Chi and Zhang, Wei and Zhu, Dashuai and Li, Zhenhua and Wang, Zhenzhen and Li, Junlang and Mei, Xuan and Xu, Wei and Cheng, Ke and Zhong, Biao}, year={2022}, month={Jan} }
 @article{huang_cheng_2022, title={Sealing the heart from the inside out}, volume={7}, ISSN={2157-846X}, url={http://dx.doi.org/10.1038/s41551-022-00981-4}, DOI={10.1038/s41551-022-00981-4}, number={2}, journal={Nature Biomedical Engineering}, publisher={Springer Science and Business Media LLC}, author={Huang, Ke and Cheng, Ke}, year={2022}, month={Dec}, pages={87–88} }
 @article{liu_menon_putcha_huang_bonilla_vora_li_zhang_wang_fletcher_et al._2022, title={Skin-Interfaced Deep-Tissue Sensing Patch via Microneedle Waveguides}, volume={6}, ISSN={["2365-709X"]}, DOI={10.1002/admt.202200468}, journal={ADVANCED MATERIALS TECHNOLOGIES}, author={Liu, Yihan and Menon, Rahul and Putcha, Arjun and Huang, Ke and Bonilla, Leonardo and Vora, Rohan and Li, Junye and Zhang, Lin and Wang, Yihang and Fletcher, Lauren and et al.}, year={2022}, month={Jun} }
 @article{chingale_cheng_huang_2021, title={3D Bioprinting Technology – One Step Closer Towards Cardiac Tissue Regeneration}, volume={8}, ISSN={2296-8016}, url={http://dx.doi.org/10.3389/fmats.2021.804134}, DOI={10.3389/fmats.2021.804134}, abstractNote={Cardiovascular diseases are one of the leading causes of death across the globe. Heart transplantation has been used for end stage heart failure patients. However, due to the lack of donors, this treatment option usually depends on multiple variables and the result varies due to immunological issues. 3D bioprinting is an emerging approach for in vitro generation of functional cardiac tissues for drug screening and cardiac regenerative therapy. There are different techniques such as extrusion, inkjet, or laser-based 3D printing that integrate multiple cell lines with different scaffolds for the construction of complex 3D structures. In this review, we discussed the recent progress and challenges in 3D bioprinting strategies for cardiac tissue engineering, including cardiac patches, in vitro cardiac models, valves, and blood vessels.}, journal={Frontiers in Materials}, publisher={Frontiers Media SA}, author={Chingale, Mira and Cheng, Ke and Huang, Ke}, year={2021} }
 @article{yao_huang_zhu_chen_jiang_zhang_mi_xuan_hu_li_et al._2021, title={A Minimally Invasive Exosome Spray Repairs Heart after Myocardial Infarction}, volume={15}, ISSN={["1936-086X"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85110404046&partnerID=MN8TOARS}, DOI={10.1021/acsnano.1c00628}, abstractNote={Myocardial infarction (MI) remains the most common cause of death worldwide. Many MI survivors will suffer from recurrent heart failure (HF), which has been recognized as a determinant of adverse prognosis. Despite the success of improved early survival after MI by primary percutaneous coronary intervention, HF after MI is becoming the major driver of late morbidity, mortality, and healthcare costs. The development of regenerative medicine has brought hope to MI treatment in the past decade. Mesenchymal stem cell (MSC)-derived exosomes have been established as an essential part of stem cell paracrine factors for heart regeneration. However, its regenerative power is hampered by low delivery efficiency to the heart. We designed, fabricated, and tested a minimally invasive exosome spray (EXOS) based on MSC exosomes and biomaterials. In a mouse model of acute myocardial infarction, EXOS improved cardiac function and reduced fibrosis, and promoted endogenous angiomyogenesis in the post-injury heart. We further tested the feasibility and safety of EXOS in a pig model. Our results indicate that EXOS is a promising strategy to deliver therapeutic exosomes for heart repair.}, number={7}, journal={ACS NANO}, publisher={American Chemical Society (ACS)}, author={Yao, Jialu and Huang, Ke and Zhu, Dashuai and Chen, Tan and Jiang, Yufeng and Zhang, Junyi and Mi, Lijie and Xuan, He and Hu, Shiqi and Li, Junlang and et al.}, year={2021}, month={Jul}, pages={11099–11111} }
 @article{allen_cullen_hawkey_mochizuki_nguyen_schechter_borst_yoder_freedman_patierno_et al._2021, title={A Zebrafish Model of Metastatic Colonization Pinpoints Cellular Mechanisms of Circulating Tumor Cell Extravasation}, volume={11}, ISSN={["2234-943X"]}, DOI={10.3389/fonc.2021.641187}, abstractNote={Metastasis is a multistep process in which cells must detach, migrate/invade local structures, intravasate, circulate, extravasate, and colonize. A full understanding of the complexity of this process has been limited by the lack of ability to study these steps in isolation with detailed molecular analyses. Leveraging a comparative oncology approach, we injected canine osteosarcoma cells into the circulation of transgenic zebrafish with fluorescent blood vessels in a biologically dynamic metastasis extravasation model. Circulating tumor cell clusters that successfully extravasated the vasculature as multicellular units were isolated under intravital imaging (n = 6). These extravasation-positive tumor cell clusters sublines were then molecularly profiled by RNA-Seq. Using a systems-level analysis, we pinpointed the downregulation of KRAS signaling, immune pathways, and extracellular matrix (ECM) organization as enriched in extravasated cells (p < 0.05). Within the extracellular matrix remodeling pathway, we identified versican ( VCAN ) as consistently upregulated and central to the ECM gene regulatory network (p < 0.05). Versican expression is prognostic for a poorer metastasis-free and overall survival in patients with osteosarcoma. Together, our results provide a novel experimental framework to study discrete steps in the metastatic process. Using this system, we identify the versican/ECM network dysregulation as a potential contributor to osteosarcoma circulating tumor cell metastasis.}, journal={FRONTIERS IN ONCOLOGY}, author={Allen, Tyler A. and Cullen, Mark M. and Hawkey, Nathan and Mochizuki, Hiroyuki and Nguyen, Lan and Schechter, Elyse and Borst, Luke and Yoder, Jeffrey A. and Freedman, Jennifer A. and Patierno, Steven R. and et al.}, year={2021}, month={Sep} }
 @article{mei_zhu_li_huang_hu_li_abad_cheng_2021, title={A fluid-powered refillable origami heart pouch for minimally invasive delivery of cell therapies in rats and pigs}, volume={2}, ISSN={["2666-6340"]}, url={https://doi.org/10.1016/j.medj.2021.10.001}, DOI={10.1016/j.medj.2021.10.001}, abstractNote={<h2>Summary</h2><h3>Background</h3> Cardiac repair after heart injury remains a big challenge, and current drug delivery to the heart is suboptimal. Repeated dosing of therapeutics is difficult due to the invasive nature of such procedures. <h3>Methods</h3> We developed a fluid-driven heart pouch with a memory-shaped microfabricated lattice structure inspired by origami. The pore size of the membrane is around 0.4 μm, which allows for the penetration of growth factors and exosomes. <h3>Findings</h3> We tested the pouch's ability to deliver mesenchymal stem cells (MSCs) in a rodent model of acute myocardial infarction and demonstrated the feasibility of minimally invasive delivery in a swine model. The pouch's semi-permeable membrane successfully protected delivered cells from their surroundings, maintaining their viability while releasing growth factors and exosomes to the infarcted site for cardiac repair. <h3>Conclusions</h3> In summary, we developed a fluid-driven heart pouch with a memory-shaped microfabricated lattice structure inspired by origami. The origami structure allowed minimally invasive delivery of the pouch to the heart and can be refilled with the therapeutic of choice. <h3>Funding</h3> This work was supported by grants from the NIH (HL123920, HL137093, HL144002, HL146153, HL147357, and HL149940 to K.C.) and the American Heart Association (18TPA34230092 and 19EIA34660286 to K.C.).}, number={11}, journal={MED}, publisher={Elsevier BV}, author={Mei, Xuan and Zhu, Dashuai and Li, Junlang and Huang, Ke and Hu, Shiqi and Li, Zhenhua and Abad, Blanca Lopez de Juan and Cheng, Ke}, year={2021}, month={Nov}, pages={1253-+} }
 @article{zhang_zhu_li_huang_hu_lutz_xie_mei_li_neal-perry_et al._2021, title={A stem cell-derived ovarian regenerative patch restores ovarian function and rescues fertility in rats with primary ovarian insufficiency}, volume={11}, ISSN={["1838-7640"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85114771196&partnerID=MN8TOARS}, DOI={10.7150/thno.61690}, abstractNote={Rationale: Primary ovarian insufficiency (POI) normally occurs before age 40 and is associated with infertility. Hormone replacement therapy is often prescribed to treat vasomotor symptom, but it cannot restore ovarian function or fertility. Stem cell therapy has been studied for the treatment of POI. However, the application of live stem cells has suffered from drawbacks, such as low cell retention/engraftment rate, risks for tumorigenicity and immunogenicity, and lack of off-the-shelf feasibility. Methods: We developed a therapeutic ovarian regenerative patch (ORP) that composed of clinically relevant hydrolysable scaffolds and synthetic mesenchymal stem cells (synMSCs), which are microparticles encapsulating the secretome from MSCs. The therapeutic potency of ORP was tested in rats with cisplatin induced POI injury. Results:In vitro studies revealed that ORP stimulated proliferation of ovarian somatic cells (OSCs) and inhibited apoptosis under injury stress. In a rat model of POI, implantation of ORP rescued fertility by restoring sexual hormone secretion, estrus cycle duration, and follicle development. Conclusion: ORP represents a cell-free, off-the-shelf, and clinically feasible treatment for POI.}, number={18}, journal={THERANOSTICS}, author={Zhang, Sichen and Zhu, Dashuai and Li, Zhenhua and Huang, Ke and Hu, Shiqi and Lutz, Halle and Xie, Mengjie and Mei, Xuan and Li, Junlang and Neal-Perry, Genevieve and et al.}, year={2021}, pages={8894–8908} }
 @article{xie_li_zhang_zhu_mei_wang_cheng_li_wang_cheng_2021, title={A trifunctional contraceptive gel enhances the safety and quality of sexual intercourse}, volume={6}, ISSN={["2452-199X"]}, url={https://doi.org/10.1016/j.bioactmat.2020.11.031}, DOI={10.1016/j.bioactmat.2020.11.031}, abstractNote={Current contraceptive methods come with a number of drawbacks, including low efficacy, in the case of commercial contraceptive gels, and a reduction in the quality of sexual intercourse, in the case of condoms. Adding pharmacologically-active agents to contraceptive gels holds the potential to improve sexual experience, and hardbor safety and hygiene. In this study, we fabricated a carbomer-based contraceptive gel consisting of three agents: tenofovir, gossypol acetate, and nitroglycerin (TGN), with pH adjusted to 4.5 (to be compatible with the vagina). In vitro, the gossypol component of the contraceptive gel proved to be an effective spermicide. When the concentration of gossypol acetate was 10 mg/ml, the spermicidal ability reached 100% after 30 s. In addition, tenofovir in the gel significantly inhibited lentiviral transfection efficiency in cell-containing media. In 6 pairs of rats, the gel successfully prevented all females from conceiving after successful mating. Moreover, increased sexual frequency and enhanced erection, which were promoted by the nitroglycerin in the components, were observed in male rats that had the gel applied to their penises. This novel TGN contraceptive gel yielded a higher contraceptive success rate than that of the commercial contraceptive gel (Contragel®). In addition, it has the added benefits to prevent sexually transmitted diseases and improve male libido and erectile function during sexual intercourse. Combining three FDA-approved and marketed agents together, our trifunctional TGN gel has a great potential for further translation and commercialization.}, number={6}, journal={BIOACTIVE MATERIALS}, publisher={Elsevier BV}, author={Xie, Mengjie and Li, Junlang and Zhang, Sichen and Zhu, Dashuai and Mei, Xuan and Wang, Zhenzhen and Cheng, Xiao and Li, Zhenhua and Wang, Shaowei and Cheng, Ke}, year={2021}, month={Jun}, pages={1777–1788} }
 @misc{zhang_zhu_mei_li_li_xie_xie_wang_cheng_2021, title={Advances in biomaterials and regenerative medicine for primary ovarian insufficiency therapy}, volume={6}, ISSN={["2452-199X"]}, url={https://doi.org/10.1016/j.bioactmat.2020.12.008}, DOI={10.1016/j.bioactmat.2020.12.008}, abstractNote={Primary ovarian insufficiency (POI) is an ovarian dysfunction that affects more than 1 % of women and is characterized by hormone imbalances that afflict women before the age of 40. The typical perimenopausal symptoms result from abnormal levels of sex hormones, especially estrogen. The most prevalent treatment is hormone replacement therapy (HRT), which can relieve symptoms and improve quality of life. However, HRT cannot restore ovarian functions, including secretion, ovulation, and fertility. Recently, as part of a developing field of regenerative medicine, stem cell therapy has been proposed for the treatment of POI. Thus, we recapitulate the literature focusing on the use of stem cells and biomaterials for POI treatment, and sum up the underlying mechanisms of action. A thorough understanding of the work already done can aid in the development of guidelines for future translational applications and clinical trials that aim to cure POI by using regenerative medicine and biomedical engineering strategies.}, number={7}, journal={BIOACTIVE MATERIALS}, publisher={Elsevier BV}, author={Zhang, Sichen and Zhu, Dashuai and Mei, Xuan and Li, Zhenhua and Li, Junlang and Xie, Mengjie and Xie, Halle Jiang Williams and Wang, Shaowei and Cheng, Ke}, year={2021}, month={Jul}, pages={1957–1972} }
 @misc{li_hu_zhu_huang_mei_abad_cheng_2021, title={All Roads Lead to Rome (the Heart): Cell Retention and Outcomes From Various Delivery Routes of Cell Therapy Products to the Heart}, volume={10}, ISSN={["2047-9980"]}, url={https://doi.org/10.1161/JAHA.120.020402}, DOI={10.1161/JAHA.120.020402}, abstractNote={In the past decades, numerous preclinical studies and several clinical trials have evidenced the feasibility of cell transplantation in treating heart diseases. Over the years, different delivery routes of cell therapy have emerged and broadened the width of the field. However, a common hurdle is shared by all current delivery routes: low cell retention. A myriad of studies confirm that cell retention plays a crucial role in the success of cell-mediated cardiac repair. It is important for any delivery route to maintain donor cells in the recipient heart for enough time to not only proliferate by themselves, but also to send paracrine signals to surrounding damaged heart cells and repair them. In this review, we first undertake an in-depth study of primary theories of cell loss, including low efficiency in cell injection, "washout" effects, and cell death, and then organize the literature from the past decade that focuses on cell transplantation to the heart using various cell delivery routes, including intracoronary injection, systemic intravenous injection, retrograde coronary venous injection, and intramyocardial injection. In addition to a recapitulation of these approaches, we also clearly evaluate their strengths and weaknesses. Furthermore, we conduct comparative research on the cell retention rate and functional outcomes of these delivery routes. Finally, we extend our discussion to state-of-the-art bioengineering techniques that enhance cell retention, as well as alternative delivery routes, such as intrapericardial delivery. A combination of these novel strategies and more accurate assessment methods will help to address the hurdle of low cell retention and boost the efficacy of cell transplantation to the heart.}, number={8}, journal={JOURNAL OF THE AMERICAN HEART ASSOCIATION}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Li, Junlang and Hu, Shiqi and Zhu, Dashuai and Huang, Ke and Mei, Xuan and Abad, Blanca Lopez de Juan and Cheng, Ke}, year={2021}, month={Apr} }
 @article{chingale_zhu_cheng_huang_2021, title={Bioengineering Technologies for Cardiac Regenerative Medicine}, volume={9}, ISSN={2296-4185}, url={http://dx.doi.org/10.3389/fbioe.2021.681705}, DOI={10.3389/fbioe.2021.681705}, abstractNote={Cardiac regenerative medicine faces big challenges such as a lack of adult cardiac stem cells, low turnover of mature cardiomyocytes, and difficulty in therapeutic delivery to the injured heart. The interaction of bioengineering and cardiac regenerative medicine offers innovative solutions to this field. For example, cell reprogramming technology has been applied by both direct and indirect routes to generate patient-specific cardiomyocytes. Various viral and non-viral vectors have been utilized for gene editing to intervene gene expression patterns during the cardiac remodeling process. Cell-derived protein factors, exosomes, and miRNAs have been isolated and delivered through engineered particles to overcome many innate limitations of live cell therapy. Protein decoration, antibody modification, and platelet membranes have been used for targeting and precision medicine. Cardiac patches have been used for transferring therapeutics with better retention and integration. Other technologies such as 3D printing and 3D culture have been used to create replaceable cardiac tissue. In this review, we discuss recent advancements in bioengineering and biotechnologies for cardiac regenerative medicine.}, journal={Frontiers in Bioengineering and Biotechnology}, publisher={Frontiers Media SA}, author={Chingale, Mira and Zhu, Dashuai and Cheng, Ke and Huang, Ke}, year={2021}, month={Jun} }
 @misc{zhu_cheng_2021, title={Cardiac Cell Therapy for Heart Repair: Should the Cells Be Left Out?}, volume={10}, ISSN={["2073-4409"]}, url={https://doi.org/10.3390/cells10030641}, DOI={10.3390/cells10030641}, abstractNote={Cardiovascular disease (CVD) is still the leading cause of death worldwide. Coronary artery occlusion, or myocardial infarction (MI) causes massive loss of cardiomyocytes. The ischemia area is eventually replaced by a fibrotic scar. From the mechanical dysfunctions of the scar in electronic transduction, contraction and compliance, pathological cardiac dilation and heart failure develops. Once end-stage heart failure occurs, the only option is to perform heart transplantation. The sequential changes are termed cardiac remodeling, and are due to the lack of endogenous regenerative actions in the adult human heart. Regenerative medicine and biomedical engineering strategies have been pursued to repair the damaged heart and to restore normal cardiac function. Such strategies include both cellular and acellular products, in combination with biomaterials. In addition, substantial progress has been made to elucidate the molecular and cellular mechanisms underlying heart repair and regeneration. In this review, we summarize and discuss current therapeutic approaches for cardiac repair and provide a perspective on novel strategies that holding potential opportunities for future research and clinical translation.}, number={3}, journal={CELLS}, publisher={MDPI AG}, author={Zhu, Dashuai and Cheng, Ke}, year={2021}, month={Mar} }
 @misc{liu_abad_cheng_2021, title={Cardiac fibrosis: Myofibroblast-mediated pathological regulation and drug delivery strategies}, volume={173}, ISSN={["1872-8294"]}, DOI={10.1016/j.addr.2021.03.021}, abstractNote={Cardiac fibrosis remains an unresolved problem in heart diseases. After initial injury, cardiac fibroblasts (CFs) are activated and subsequently differentiate into myofibroblasts (myoFbs) that are major mediator cells in the pathological remodeling. MyoFbs exhibit proliferative and secretive characteristics, and contribute to extracellular matrix (ECM) turnover, collagen deposition. The persistent functions of myoFbs lead to fibrotic scars and cardiac dysfunction. The anti-fibrotic treatment is hindered by the elusive mechanism of fibrosis and lack of specific targets on myoFbs. In this review, we will outline the progress of cardiac fibrosis and its contributions to the heart failure. We will also shed light on the role of myoFbs in the regulation of adverse remodeling. The communication between myoFbs and other cells that are involved in the heart injury and repair respectively will be reviewed in detail. Then, recently developed therapeutic strategies to treat fibrosis will be summarized such as i) chimeric antigen receptor T cell (CAR-T) therapy with an optimal target on myoFbs, ii) direct reprogramming from stem cells to quiescent CFs, iii) “off-target” small molecular drugs. The application of nano/micro technology will be discussed as well, which is involved in the construction of cell-based biomimic platforms and “pleiotropic” drug delivery systems.}, journal={ADVANCED DRUG DELIVERY REVIEWS}, author={Liu, Mengrui and Abad, Blanca Lopez de Juan and Cheng, Ke}, year={2021}, month={Jun}, pages={504–519} }
 @article{carter_popowski_cheng_greenbaum_ligler_moatti_2021, title={Enhancement of Bone Regeneration Through the Converse Piezoelectric Effect, A Novel Approach for Applying Mechanical Stimulation}, volume={9}, ISSN={["2576-3113"]}, url={https://doi.org/10.1089/bioe.2021.0019}, DOI={10.1089/bioe.2021.0019}, abstractNote={Serious bone injuries have devastating effects on the lives of patients including limiting working ability and high cost. Orthopedic implants can aid in healing injuries to an extent that exceeds the natural regenerative capabilities of bone to repair fractures or large bone defects. Autografts and allografts are the standard implants used, but disadvantages such as donor site complications, a limited quantity of transplantable bone, and high costs have led to an increased demand for synthetic bone graft substitutes. However, replicating the complex physiological properties of biological bone, much less recapitulating its complex tissue functions, is challenging. Extensive efforts to design biocompatible implants that mimic the natural healing processes in bone have led to the investigation of piezoelectric smart materials because the bone has natural piezoelectric properties. Piezoelectric materials facilitate bone regeneration either by accumulating electric charge in response to mechanical stress, which mimics bioelectric signals through the direct piezoelectric effect or by providing mechanical stimulation in response to electrical stimulation through the converse piezoelectric effect. Although both effects are beneficial, the converse piezoelectric effect can address bone atrophy from stress shielding and immobility by improving the mechanical response of a healing defect. Mechanical stimulation has a positive impact on bone regeneration by activating cellular pathways that increase bone formation and decrease bone resorption. This review will highlight the potential of the converse piezoelectric effect to enhance bone regeneration by discussing the activation of beneficial cellular pathways, the properties of piezoelectric biomaterials, and the potential for the more effective administration of the converse piezoelectric effect using wireless control.}, journal={BIOELECTRICITY}, publisher={Mary Ann Liebert Inc}, author={Carter, Amber and Popowski, Kristen and Cheng, Ke and Greenbaum, Alon and Ligler, Frances S. and Moatti, Adele}, year={2021}, month={Sep} }
 @misc{popowski_dinh_george_lutz_cheng_2021, title={Exosome therapeutics for COVID-19 and respiratory viruses}, volume={2}, ISSN={["2688-268X"]}, url={https://doi.org/10.1002/VIW.20200186}, DOI={10.1002/VIW.20200186}, abstractNote={Respiratory viral diseases are a leading cause of mortality in humans. They have proven to drive pandemic risk due to their complex transmission factors and viral evolution. However, the slow production of effective antiviral drugs and vaccines allows for outbreaks of these diseases, emphasizing a critical need for refined antiviral therapeutics. The delivery of exosomes, a naturally secreted extracellular vesicle, yields therapeutic effects for a variety of diseases, including viral infection. Exosomes and viruses utilize similar endosomal sorting pathways and mechanisms, providing exosomes with the potential to serve as a therapeutic that can target, bind, and suppress cellular uptake of various viruses including the novel severe acute respiratory syndrome coronavirus 2. Here, we review the relationship between exosomes and respiratory viruses, describe potential exosome therapeutics for viral infections, and summarize progress toward clinical translation for lung-derived exosome therapeutics.}, number={3}, journal={VIEW}, publisher={Wiley}, author={Popowski, Kristen D. and Dinh, Phuong-Uyen C. and George, Arianna and Lutz, Halle and Cheng, Ke}, year={2021}, month={Jun} }
 @article{hu_li_shen_zhu_huang_su_dinh_cores_cheng_2021, title={Exosome-eluting stents for vascular healing after ischaemic injury}, volume={5}, ISSN={["2157-846X"]}, url={https://doi.org/10.1038/s41551-021-00705-0}, DOI={10.1038/s41551-021-00705-0}, abstractNote={Drug-eluting stents implanted after ischaemic injury reduce the proliferation of endothelial cells and vascular smooth muscle cells and thus neointimal hyperplasia. However, the eluted drug also slows down the re-endothelialization process, delays arterial healing and can increase the risk of late restenosis. Here we show that stents releasing exosomes derived from mesenchymal stem cells in the presence of reactive oxygen species enhance vascular healing in rats with renal ischaemia-reperfusion injury, promoting endothelial cell tube formation and proliferation, and impairing the migration of smooth muscle cells. Compared with drug-eluting stents and bare-metal stents, the exosome-coated stents accelerated re-endothelialization and decreased in-stent restenosis 28 days after implantation. We also show that exosome-eluting stents implanted in the abdominal aorta of rats with unilateral hindlimb ischaemia regulated macrophage polarization, reduced local vascular and systemic inflammation, and promoted muscle tissue repair.}, number={10}, journal={NATURE BIOMEDICAL ENGINEERING}, publisher={Springer Science and Business Media LLC}, author={Hu, Shiqi and Li, Zhenhua and Shen, Deliang and Zhu, Dashuai and Huang, Ke and Su, Teng and Dinh, Phuong-Uyen and Cores, Jhon and Cheng, Ke}, year={2021}, month={Oct}, pages={1174–1188} }
 @article{wang_hu_li_zhu_wang_cores_cheng_liu_huang_2021, title={Extruded Mesenchymal Stem Cell Nanovesicles Are Equally Potent to Natural Extracellular Vesicles in Cardiac Repair}, volume={13}, ISSN={["1944-8252"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85119954105&partnerID=MN8TOARS}, DOI={10.1021/acsami.1c08044}, abstractNote={Mesenchymal stem cells (MSCs) repair injured tissues mainly through their paracrine actions. One of the important paracrine components of MSC secretomes is the extracellular vesicle (EV). The therapeutic potential of MSC-EVs has been established in various cardiac injury preclinical models. However, the large-scale production of EVs remains a challenge. We sought to develop a scale-up friendly method to generate a large number of therapeutic nanovesicles from MSCs by extrusion. Those extruded nanovesicles (NVs) are miniature versions of MSCs in terms of surface marker expression. The yield of NVs is 20-fold more than that of EVs. In vitro, cell-based assays demonstrated the myocardial protective effects and therapeutic potential of NVs. Intramyocardial delivery of NVs in the injured heart after ischemia-reperfusion led to a reduction in scar sizes and preservation of cardiac functions. Such therapeutic benefits are similar to those injected with natural EVs from the same MSC parental cells. In addition, NV therapy promoted angiogenesis and proliferation of cardiomyocytes in the post-injury heart. In summary, extrusion is a highly efficient method to generate a large quantity of therapeutic NVs that can potentially replace extracellular vesicles in regenerative medicine applications.}, number={47}, journal={ACS APPLIED MATERIALS & INTERFACES}, publisher={American Chemical Society (ACS)}, author={Wang, Xianyun and Hu, Shiqi and Li, Junlang and Zhu, Dashuai and Wang, Zhenzhen and Cores, Jhon and Cheng, Ke and Liu, Gang and Huang, Ke}, year={2021}, month={Dec}, pages={55767–55779} }
 @article{hu_qiao_cheng_2021, title={Generation and Manipulation of Exosomes}, volume={2158}, ISBN={["978-1-0716-0667-4"]}, ISSN={["1940-6029"]}, DOI={10.1007/978-1-0716-0668-1_22}, abstractNote={Exosomes are membrane-bound nano-vehicles shed by most eukaryotic cells. Exosomes contain specific proteins and RNAs from parent cells, and they play key signaling roles in cellular development, modulation, and tissue regeneration. Attempts to isolate and modify exosomes to increase their targeting efficiency to specific tissue are still in their infancy. Here, we describe generation of exosomes from biopsy, isolation of exosomes by centrifugal ultrafiltration method, and approaches for manipulation of cardiac homing exosomes by chemical engineering for the treatment of myocardial infarction.}, journal={CARDIAC REGENERATION}, author={Hu, Shiqi and Qiao, Li and Cheng, Ke}, year={2021}, pages={295–305} }
 @article{allen_cheng_2021, title={Imaging and Isolation of Extravasation-Participating Endothelial and Melanoma Cells During Angiopellosis}, volume={2265}, ISBN={["978-1-0716-1204-0"]}, ISSN={["1940-6029"]}, DOI={10.1007/978-1-0716-1205-7_30}, abstractNote={Cancer mortality rates are primarily a result of cancer metastasis. Recent advances in microscopy technology allow for the imaging of circulating tumor cells (CTCs) as they extravasate (exit) blood vessels, a key step in the metastasis process. Here, we describe the use of intravital microscopy techniques to image and isolate both extravasating melanoma CTCs and the extravasation-participating endothelial cells. These techniques can be used as a means to study cancer metastasis and as a screening tool for anticancer therapeutics.}, journal={MELANOMA}, author={Allen, Tyler A. and Cheng, Ke}, year={2021}, pages={417–425} }
 @article{li_zhu_hui_bi_yu_huang_hu_wang_caranasos_rossi_et al._2021, title={Injection of ROS-Responsive Hydrogel Loaded with Basic Fibroblast Growth Factor into the Pericardial Cavity for Heart Repair}, volume={31}, ISSN={["1616-3028"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85100498082&partnerID=MN8TOARS}, DOI={10.1002/adfm.202004377}, abstractNote={Myocardial infarction, among other ischemic heart diseases, is the major cause of mortality and morbidity for patients who have heart diseases. Timely reperfusion of the ischemic myocardium is the most effective way to treat myocardial infarction. However, blood reperfusion to the ischemic tissues leads to an overproduction of toxic reactive oxygen species (ROS), which can further exacerbate myocardial damage on top of ischemic injury. ROS has been used as a diagnostic marker and therapeutic target for ischemia-reperfusion (I/R) injury and as an environmental stimulus to trigger drug release. In this study, a ROS-sensitive cross-linked poly(vinyl alcohol) (PVA) hydrogel is synthesized to deliver basic fibroblast growth factor (bFGF) for myocardial repair. The therapeutic gel is injected into the pericardial cavity. Upon delivery, the hydrogel spread on the surface of the heart and form an epicardiac patch in situ. In a rat model of I/R injury, bFGF released from the gel could penetrate the myocardium. Such intervention protects cardiac function and reduces fibrosis in the post-I/R heart, with enhanced angiomyogenesis. Furthermore, the safety and feasibility of minimally invasive injection and access into the pericardial cavity in both pigs and human patients are demonstrated.}, number={15}, journal={ADVANCED FUNCTIONAL MATERIALS}, author={Li, Zhenhua and Zhu, Dashuai and Hui, Qi and Bi, Jianing and Yu, Bingjie and Huang, Zhen and Hu, Shiqi and Wang, Zhenzhen and Caranasos, Thomas and Rossi, Joseph and et al.}, year={2021}, month={Apr} }
 @article{zhu_li_huang_caranasos_rossi_cheng_2021, title={Minimally invasive delivery of therapeutic agents by hydrogel injection into the pericardial cavity for cardiac repair}, volume={12}, ISSN={["2041-1723"]}, url={https://doi.org/10.1038/s41467-021-21682-7}, DOI={10.1038/s41467-021-21682-7}, abstractNote={Abstract Cardiac patches are an effective way to deliver therapeutics to the heart. However, such procedures are normally invasive and difficult to perform. Here, we develop and test a method to utilize the pericardial cavity as a natural “mold” for in situ cardiac patch formation after intrapericardial injection of therapeutics in biocompatible hydrogels. In rodent models of myocardial infarction, we demonstrate that intrapericardial injection is an effective and safe method to deliver hydrogels containing induced pluripotent stem cells-derived cardiac progenitor cells or mesenchymal stem cells-derived exosomes. After injection, the hydrogels form a cardiac patch-like structure in the pericardial cavity, mitigating immune response and increasing the cardiac retention of the therapeutics. With robust cardiovascular repair and stimulation of epicardium-derived cells, the delivered therapeutics mitigate cardiac remodeling and improve cardiac functions post myocardial infarction. Furthermore, we demonstrate the feasibility of minimally-invasive intrapericardial injection in a clinically-relevant porcine model. Collectively, our study establishes intrapericardial injection as a safe and effective method to deliver therapeutic-bearing hydrogels to the heart for cardiac repair.}, number={1}, journal={NATURE COMMUNICATIONS}, author={Zhu, Dashuai and Li, Zhenhua and Huang, Ke and Caranasos, Thomas G. and Rossi, Joseph S. and Cheng, Ke}, year={2021}, month={Mar} }
 @article{hu_wang_li_zhu_cores_wang_li_mei_cheng_su_et al._2021, title={Platelet membrane and stem cell exosome hybrids enhance cellular uptake and targeting to heart injury}, volume={39}, ISSN={["1878-044X"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85107566346&partnerID=MN8TOARS}, DOI={10.1016/j.nantod.2021.101210}, abstractNote={• Platelet membrane modification enhanced the accumulation of exosomes in injured tissues. • Platelet membrane substantially enhanced macropinocytosis-mediated cellular internalization of exosomes. • Platelet membrane hybrid improved the pharmacokinetic of stem cell derived exosomes. • This is a simple, fast, and translatable approach to modify therapeutic exosomes to make them disease targetable. We used platelet membrane to modify exosomes and rely on the natural “injury finding” ability of platelets to target the hybrid exosomes to vascular injury under myocardial infarction. Interestingly, we found that platelet membrane improved cellular binding and internalization of exosomes through enhanced macropinocytosis-mediated cellular internalization by endothelial cells and cardiomyocytes, but not by macrophages. Such modified exosomes showed improved targeting and functional benefits in vitro, and in a mouse myocardial infarction model in vivo, as compared to unmodified naive exosomes. Exosomes from mesenchymal stem cells have been widely studied as therapeutics to treat myocardial infarction. However, exosomes injected for therapeutic purposes face a number of challenges, including competition from endogenous exosomes, and the internalization/clearance by the mononuclear phagocyte system. There is also a lack of targeting. In this study, we hybridized stem cell-derived exosomes with platelet membranes to enhance their ability to target the injured heart and to reduce uptake by macrophages. Furthermore, we found that hybridization with platelet membranes induces macropinocytosis, enhancing the cellular uptake of exosomes by endothelial cells and cardiomyocytes drastically. In vivo studies showed the cardiac targeting ability of hybrid exosomes in a mouse model of myocardial infarction injury. Lastly, we determined cardiac functions and performed immunohistochemistry to confirm an enahnced therapeutic potency of platelet membrane modified exosomes as compared to non-modified exosomes. Our studies provide proof-of-concept data and a universal approach to enhance the binding and accumulation of exosomes in injured tissues.}, journal={NANO TODAY}, author={Hu, Shiqi and Wang, Xianyun and Li, Zhenhua and Zhu, Dashuai and Cores, Jhon and Wang, Zhenzhen and Li, Junlang and Mei, Xuan and Cheng, Xiao and Su, Teng and et al.}, year={2021}, month={Aug} }
 @article{hsu_huang_cheng_2021, title={Resuscitating the Field of Cardiac Regeneration: Seeking Answers from Basic Biology}, volume={6}, ISSN={2701-0198 2701-0198}, url={http://dx.doi.org/10.1002/adbi.202101133}, DOI={10.1002/adbi.202101133}, abstractNote={Heart failure (HF) is one of the leading causes for hospital admissions worldwide. HF patients are classified based on the chronic changes in left ventricular ejection fraction (LVEF) as preserved (LVEF ≥ 50%), reduced (LVEF ≤ 40%), or mid-ranged (40% < LVEF < 50%) HFs. Treatments nowadays can prevent HFrEF progress, whereas only a few of the treatments have been proven to be effective in improving the survival of HFpEF. In this review, numerous mediators involved in the pathogenesis of HF are summarized. The regional upstream signaling and their diagnostic and therapeutic potential are also discussed. Additionally, the recent challenges and development in cardiac regenerative therapy that hold opportunities for future research and clinical translation are discussed.}, number={2}, journal={Advanced Biology}, publisher={Wiley}, author={Hsu, Yaching and Huang, Ke and Cheng, Ke}, year={2021}, month={Dec}, pages={2101133} }
 @article{zheng_fan_liu_zhang_dai_li_zhou_hu_yang_jin_et al._2021, title={Self-Propelled and Near-Infrared-Phototaxic Photosynthetic Bacteria as Photothermal Agents for Hypoxia-Targeted Cancer Therapy}, volume={15}, ISBN={1936-086X}, DOI={10.1021/acsnano.0c08068}, abstractNote={Hypoxia can increase the resistance of tumor cells to radiotherapy and chemotherapy. However, the dense extracellular matrix, high interstitial fluid pressure, and irregular blood supply often serve as physical barriers to inhibit penetration of drugs or nanodrugs across tumor blood microvessels into hypoxic regions. Therefore, it is of great significance and highly desirable to improve the efficiency of hypoxia-targeted therapy. In this work, living photosynthetic bacteria (PSB) are utilized as hypoxia-targeted carriers for hypoxic tumor therapy due to their near-infrared (NIR) chemotaxis and their physiological characteristics as facultative aerobes. More interestingly, we discovered that PSB can serve as a kind of photothermal agent to generate heat through nonradiative relaxation pathways due to their strong photoabsorption in the NIR region. Therefore, PSB integrate the properties of hypoxia targeting and photothermal therapeutic agents in an all-in-one manner, and no postmodification is needed to achieve hypoxia-targeted cancer therapy. Moreover, as natural bacteria, noncytotoxic PSB were found to enhance immune response that induced the infiltration of cytotoxicity T lymphocyte. Our results indicate PSB specifically accumulate in hypoxic tumor regions, and they show a high efficiency in the elimination of cancer cells. This proof of concept may provide a smart therapeutic system in the field of hypoxia-targeted photothermal therapeutic platforms.}, number={1}, journal={ACS NANO}, author={Zheng, Pengli and Fan, Miao and Liu, Huifang and Zhang, Yinghua and Dai, Xinyue and Li, Hang and Zhou, Xiaohan and Hu, Shiqi and Yang, Xinjian and Jin, Yi and et al.}, year={2021}, pages={1100–1110} }
 @misc{cheng_cheng_2021, title={Visualizing cancer extravasation: from mechanistic studies to drug development}, volume={40}, ISSN={["1573-7233"]}, DOI={10.1007/s10555-020-09942-2}, abstractNote={Metastasis is a multistep process that accounts for the majority of cancer-related death. By the end of metastasize dissemination, circulating tumor cells (CTC) need to extravasate the blood vessels at metastatic sites to form new colonization. Although cancer cell extravasation is a crucial step in cancer metastasis, it has not been successfully targeted by current anti-metastasis strategies due to the lack of a thorough understanding of the molecular mechanisms that regulate this process. This review focuses on recent progress in cancer extravasation visualization techniques, including the development of both in vitro and in vivo cancer extravasation models, that shed light on the underlying mechanisms. Specifically, multiple cancer extravasation stages, such as the adhesion to the endothelium and transendothelial migration, are successfully probed using these technologies. Moreover, the roles of different cell adhesive molecules, chemokines, and growth factors, as well as the mechanical factors in these stages are well illustrated. Deeper understandings of cancer extravasation mechanisms offer us new opportunities to escalate the discovery of anti-extravasation drugs and therapies and improve the prognosis of cancer patients.}, number={1}, journal={CANCER AND METASTASIS REVIEWS}, author={Cheng, Xiao and Cheng, Ke}, year={2021}, month={Mar}, pages={71–88} }
 @misc{mahgoub_razmara_bitaraf_norouzi_montazeri_behzadi-andouhjerdi_falahati_cheng_haik_hasan_et al._2020, title={Advances of exosome isolation techniques in lung cancer}, volume={47}, ISSN={["1573-4978"]}, DOI={10.1007/s11033-020-05715-w}, number={9}, journal={MOLECULAR BIOLOGY REPORTS}, author={Mahgoub, Elham O. and Razmara, Ehsan and Bitaraf, Amirreza and Norouzi, Fahimeh-Sadat and Montazeri, Maryam and Behzadi-Andouhjerdi, Roudabeh and Falahati, Mojtaba and Cheng, Ke and Haik, Yousif and Hasan, Anwarul and et al.}, year={2020}, month={Sep}, pages={7229–7251} }
 @article{huang_wang_li_tian_xu_xu_xiong_chen_qian_jin_et al._2020, title={Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction via up-regulating long non-coding RNA H19}, volume={116}, ISSN={["1755-3245"]}, DOI={10.1093/cvr/cvz139}, abstractNote={Abstract Aims Naturally secreted nanovesicles, known as exosomes, play important roles in stem cell-mediated cardioprotection. We have previously demonstrated that atorvastatin (ATV) pretreatment improved the cardioprotective effects of mesenchymal stem cells (MSCs) in a rat model of acute myocardial infarction (AMI). The aim of this study was to investigate if exosomes derived from ATV-pretreated MSCs exhibit more potent cardioprotective function in a rat model of AMI and if so to explore the underlying mechanisms. Methods and results Exosomes were isolated from control MSCs (MSC-Exo) and ATV-pretreated MSCs (MSCATV-Exo) and were then delivered to endothelial cells and cardiomyocytes in vitro under hypoxia and serum deprivation (H/SD) condition or in vivo in an acutely infarcted Sprague-Dawley rat heart. Regulatory genes and pathways activated by ATV pretreatment were explored using genomics approaches and functional studies. In vitro, MSCATV-Exo accelerated migration, tube-like structure formation, and increased survival of endothelial cells but not cardiomyocytes, whereas the exosomes derived from MSCATV-Exo-treated endothelial cells prevented cardiomyocytes from H/SD-induced apoptosis. In a rat AMI model, MSCATV-Exo resulted in improved recovery in cardiac function, further reduction in infarct size and reduced cardiomyocyte apoptosis compared to MSC-Exo. In addition, MSCATV-Exo promoted angiogenesis and inhibited the elevation of IL-6 and TNF-α in the peri-infarct region. Mechanistically, we identified lncRNA H19 as a mediator of the role of MSCATV-Exo in regulating expression of miR-675 and activation of proangiogenic factor VEGF and intercellular adhesion molecule-1. Consistently, the cardioprotective effects of MSCATV-Exo was abrogated when lncRNA H19 was depleted in the ATV-pretreated MSCs and was mimicked by overexpression of lncRNA H19. Conclusion Exosomes obtained from ATV-pretreated MSCs have significantly enhanced therapeutic efficacy for treatment of AMI possibly through promoting endothelial cell function. LncRNA H19 mediates, at least partially, the cardioprotective roles of MSCATV-Exo in promoting angiogenesis.}, number={2}, journal={CARDIOVASCULAR RESEARCH}, author={Huang, Peisen and Wang, Li and Li, Qing and Tian, Xiaqiu and Xu, Jun and Xu, Junyan and Xiong, Yuyan and Chen, Guihao and Qian, Haiyan and Jin, Chen and et al.}, year={2020}, month={Feb}, pages={353–367} }
 @article{su_huang_mathews_scharf_hu_li_frame_cores_dinh_daniele_et al._2020, title={Cardiac Stromal Cell Patch Integrated with Engineered Microvessels Improves Recovery from Myocardial Infarction in Rats and Pigs}, volume={6}, ISSN={["2373-9878"]}, DOI={10.1021/acsbiomaterials.0c00942}, abstractNote={The vascularized cardiac patch strategy is promising for ischemic heart repair after myocardial infarction (MI), but current fabrication processes are quite complicated. Vascularized cardiac patches that can promote concurrent restoration of both the myocardium and vasculature at the injured site in a large animal model remain elusive. The safety and therapeutic benefits of a cardiac stromal cell patch integrated with engineered biomimetic microvessels (BMVs) were determined for treating MI. By leveraging a microfluidic method employing hydrodynamic focusing, we constructed the endothelialized microvessels and then encapsulated them together with therapeutic cardiosphere-derived stromal cells (CSCs) in a fibrin gel to generate a prevascularized cardiac stromal cell patch (BMV-CSC patch). We showed that BMV-CSC patch transplantation significantly promoted cardiac function, reduced scar size, increased viable myocardial tissue, promoted neovascularization, and suppressed inflammation in rat and porcine MI models, demonstrating enhanced therapeutic efficacy compared to conventional cardiac stromal cell patches. BMV-CSC patches did not increase renal and hepatic toxicity or exhibit immunogenicity. We noted a significant increase in endogenous progenitor cell recruitment to the peri-infarct region of the porcine hearts treated with BMV-CSC patch as compared to those that received control treatments. These findings establish the BMV-CSC patch as a novel engineered-tissue therapeutic for ischemic tissue repair.}, number={11}, journal={ACS BIOMATERIALS SCIENCE & ENGINEERING}, author={Su, Teng and Huang, Ke and Mathews, Kyle G. and Scharf, Valery F. and Hu, Shiqi and Li, Zhenhua and Frame, Brianna N. and Cores, Jhon and Dinh, Phuong-Uyen and Daniele, Michael A. and et al.}, year={2020}, month={Nov}, pages={6309–6320} }
 @article{hu_li_lutz_huang_su_cores_dinh_cheng_2020, title={Dermal exosomes containing miR-218-5p promote hair regeneration by regulating beta-catenin signaling}, volume={6}, ISSN={["2375-2548"]}, url={https://doi.org/10.1126/sciadv.aba1685}, DOI={10.1126/sciadv.aba1685}, abstractNote={The progression in the hair follicle cycle from the telogen to the anagen phase is the key to regulating hair regrowth. Dermal papilla (DP) cells support hair growth and regulate the hair cycle. However, they gradually lose key inductive properties upon culture. DP cells can partially restore their capacity to promote hair regrowth after being subjected to spheroid culture. In this study, results revealed that DP spheroids are effective at inducing the progression of the hair follicle cycle from telogen to anagen compared with just DP cell or minoxidil treatment. Because of the importance of paracrine signaling in this process, secretome and exosomes were isolated from DP cell culture, and their therapeutic efficacies were investigated. We demonstrated that miR-218-5p was notably up-regulated in DP spheroid-derived exosomes. Western blot and immunofluorescence imaging were used to demonstrate that DP spheroid-derived exosomes up-regulated β-catenin, promoting the development of hair follicles.}, number={30}, journal={SCIENCE ADVANCES}, publisher={American Association for the Advancement of Science (AAAS)}, author={Hu, Shiqi and Li, Zhenhua and Lutz, Halle and Huang, Ke and Su, Teng and Cores, Jhon and Dinh, Phuong-Uyen Cao and Cheng, Ke}, year={2020}, month={Jul} }
 @misc{li_hu_cheng_2020, title={Engineering better stem cell therapies for treating heart diseases}, volume={8}, ISSN={["2305-5847"]}, DOI={10.21037/atm.2020.03.44}, abstractNote={For decades, stem cells and their byproducts have shown efficacy in repairing tissues and organs in numerous pre-clinical studies and some clinical trials, providing hope for possible cures for many important diseases. However, the translation of stem cell therapy for heart diseases from bench to bed is still hampered by several limitations. The therapeutic benefits of stem cells are mediated by a combo of mechanisms. In this review, we will provide a brief summary of stem cell therapies for ischemic heart disease. Basically, we will talk about these barriers for the clinical application of stem cell-based therapies, the investigation of mechanisms behind stem-cell based cardiac regeneration and also, what bioengineers can do and have been doing on the translational stage of stem cell therapies for heart repair.}, number={8}, journal={ANNALS OF TRANSLATIONAL MEDICINE}, author={Li, Junlang and Hu, Shiqi and Cheng, Ke}, year={2020}, month={Apr} }
 @misc{popowski_lutz_hu_george_dinh_cheng_2020, title={Exosome therapeutics for lung regenerative medicine}, volume={9}, ISSN={["2001-3078"]}, url={https://doi.org/10.1080/20013078.2020.1785161}, DOI={10.1080/20013078.2020.1785161}, abstractNote={Exosomes are 30 to 100 nm extracellular vesicles that are secreted by many cell types. Initially viewed as cellular garbage with no biological functions, exosomes are now recognized for their thera...}, number={1}, journal={JOURNAL OF EXTRACELLULAR VESICLES}, publisher={Wiley}, author={Popowski, Kristen and Lutz, Halle and Hu, Shiqi and George, Arianna and Dinh, Phuong-Uyen and Cheng, Ke}, year={2020}, month={Jan} }
 @article{dinh_paudel_brochu_popowski_gracieux_cores_huang_hensley_harrell_vandergriff_et al._2020, title={Inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis}, volume={11}, ISSN={["2041-1723"]}, url={http://dx.doi.org/10.1038/s41467-020-14344-7}, DOI={10.1038/s41467-020-14344-7}, abstractNote={Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal and incurable form of interstitial lung disease in which persistent injury results in scar tissue formation. As fibrosis thickens, the lung tissue loses the ability to facilitate gas exchange and provide cells with needed oxygen. Currently, IPF has few treatment options and no effective therapies, aside from lung transplant. Here we present a series of studies utilizing lung spheroid cell-secretome (LSC-Sec) and exosomes (LSC-Exo) by inhalation to treat different models of lung injury and fibrosis. Analysis reveals that LSC-Sec and LSC-Exo treatments could attenuate and resolve bleomycin- and silica-induced fibrosis by reestablishing normal alveolar structure and decreasing both collagen accumulation and myofibroblast proliferation. Additionally, LSC-Sec and LSC-Exo exhibit superior therapeutic benefits than their counterparts derived from mesenchymal stem cells in some measures. We showed that an inhalation treatment of secretome and exosome exhibited therapeutic potential for lung regeneration in two experimental models of pulmonary fibrosis.}, number={1}, journal={NATURE COMMUNICATIONS}, publisher={Springer Science and Business Media LLC}, author={Dinh, Phuong-Uyen C. and Paudel, Dipti and Brochu, Hayden and Popowski, Kristen D. and Gracieux, M. Cyndell and Cores, Jhon and Huang, Ke and Hensley, M. Taylor and Harrell, Erin and Vandergriff, Adam C. and et al.}, year={2020}, month={Feb} }
 @article{liang_li_ren_jia_guo_li_zhang_hu_zhu_shen_et al._2020, title={Light-triggered NO-releasing nanoparticles for treating mice with liver fibrosis}, volume={13}, ISSN={["1998-0000"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85086369757&partnerID=MN8TOARS}, DOI={10.1007/s12274-020-2833-6}, number={8}, journal={NANO RESEARCH}, author={Liang, Hongxia and Li, Zhenhua and Ren, Zhigang and Jia, Qiaodi and Guo, Linna and Li, Shasha and Zhang, Hongyu and Hu, Shiqi and Zhu, Dashuai and Shen, Deliang and et al.}, year={2020}, month={Aug}, pages={2197–2202} }
 @misc{mei_cheng_2020, title={Recent Development in Therapeutic Cardiac Patches}, volume={7}, ISSN={["2297-055X"]}, DOI={10.3389/fcvm.2020.610364}, abstractNote={For the past decades, heart diseases remain the leading cause of death worldwide. In the adult mammalian heart, damaged cardiomyocytes will be replaced by non-contractile fibrotic scar tissues due to the poor regenerative ability of heart, causing heart failure subsequently. The development of tissue engineering has launched a new medical innovation for heart regeneration. As one of the most outstanding technology, cardiac patches hold the potential to restore cardiac function clinically. Consisted of two components: therapeutic ingredients and substrate scaffolds, the fabrication of cardiac patches requires both advanced bioactive molecules and biomaterials. In this review, we will present the most state-of-the-art cardiac patches and analysis their compositional details. The therapeutic ingredients will be discussed from cell sources to bioactive molecules. In the meanwhile, the recent advances to obtain scaffold biomaterials will be highlighted, including synthetic and natural materials. Also, we have focused on the challenges and potential strategies to fabricate clinically applicable cardiac patches.}, journal={FRONTIERS IN CARDIOVASCULAR MEDICINE}, author={Mei, Xuan and Cheng, Ke}, year={2020}, month={Nov} }
 @article{li_hu_huang_su_cores_cheng_2020, title={Targeted anti-IL-1 beta platelet microparticles for cardiac detoxing and repair}, volume={6}, ISSN={["2375-2548"]}, url={https://doi.org/10.1126/sciadv.aay0589}, DOI={10.1126/sciadv.aay0589}, abstractNote={Platelet microparticles are used to deliver IL-1β antibodies to myocardial infarction for cardiac detoxing and repair.}, number={6}, journal={SCIENCE ADVANCES}, publisher={American Association for the Advancement of Science (AAAS)}, author={Li, Zhenhua and Hu, Shiqi and Huang, Ke and Su, Teng and Cores, Jhon and Cheng, Ke}, year={2020}, month={Feb} }
 @article{qiao_hu_huang_su_li_vandergriff_cores_dinh_allen_shen_et al._2020, title={Tumor cell-derived exosomes home to their cells of origin and can be used as Trojan horses to deliver cancer drugs}, volume={10}, ISSN={["1838-7640"]}, DOI={10.7150/thno.39434}, abstractNote={Cancer is the second leading cause of death worldwide and patients are in urgent need of therapies that can effectively target cancer with minimal off-target side effects. Exosomes are extracellular nano-shuttles that facilitate intercellular communication between cells and organs. It has been established that tumor-derived exosomes contain a similar protein and lipid composition to that of the cells that secrete them, indicating that exosomes might be uniquely employed as carriers for anti-cancer therapeutics. Methods: We isolated exosomes from two cancer cell lines, then co-cultured each type of cancer cells with these two kinds of exosomes and quantified exosome. HT1080 or Hela exosomes were systemically injected to Nude mice bearing a subcutaneous HT1080 tumor to investigate their cancer-homing behavior. Moreover, cancer cell-derived exosomes were engineered to carry Doxil (a common chemotherapy drug), known as D-exo, were used to detect their target and therapeutic efficacy as anti-cancer drugs. Exosome proteome array analysis were used to reveal the mechanism underly this phenomenon. Results: Exosomes derived from cancer cells fuse preferentially with their parent cancer cells, in vitro. Systemically injected tumor-derived exosomes home to their original tumor tissues. Moreover, compared to Doxil alone, the drug-loaded exosomes showed enhanced therapeutic retention in tumor tissues and eradicated them more effectively in nude mice. Exosome proteome array analysis revealed distinct integrin expression patterns, which might shed light on the underlying mechanisms that explain the exosomal cancer-homing behavior. Conclusion: Here we demonstrate that the exosomes' ability to target the parent cancer is a phenomenon that opens up new ways to devise targeted therapies to deliver anti-tumor drugs.}, number={8}, journal={THERANOSTICS}, author={Qiao, Li and Hu, Shiqi and Huang, Ke and Su, Teng and Li, Zhenhua and Vandergriff, Adam and Cores, Jhon and Dinh, Phuong-Uyen and Allen, Tyler and Shen, Deliang and et al.}, year={2020}, pages={3474–3487} }
 @article{shen_li_hu_huang_su_liang_liu_cheng_2019, title={Antibody-Armed Platelets for the Regenerative Targeting of Endogenous Stem Cells}, volume={19}, ISSN={["1530-6992"]}, DOI={10.1021/acs.nanolett.8b04970}, abstractNote={Stem cell therapies have shown promise in treating acute and chronic ischemic heart disease. However, current therapies are limited by the low retention and poor integration of injected cells in the injured tissue. Taking advantage of the natural infarct-homing ability of platelets, we engineered CD34 antibody-linked platelets (P-CD34) to capture circulating CD34-positive endogenous stem cells and direct them to the injured heart. In vitro, P-CD34 could bind to damaged aortas and capture endogenous stem cells in whole blood. In a mouse model of acute myocardial infarction, P-CD34 accumulated in the injured heart after intravenous administration, leading to a concentration of endogenous CD34 stem cells in the injured heart for effective heart repair. This represents a new technology for endogenous stem cell therapy.}, number={3}, journal={NANO LETTERS}, author={Shen, Deliang and Li, Zhenhua and Hu, Shiqi and Huang, Ke and Su, Teng and Liang, Hongxia and Liu, Feiran and Cheng, Ke}, year={2019}, month={Mar}, pages={1883–1891} }
 @article{su_huang_ma_liang_dinh_chen_shen_allen_qiao_li_et al._2019, title={Biomimetics: Platelet-Inspired Nanocells for Targeted Heart Repair After Ischemia/Reperfusion Injury (Adv. Funct. Mater. 4/2019)}, volume={29}, ISSN={1616-301X}, url={http://dx.doi.org/10.1002/ADFM.201970019}, DOI={10.1002/ADFM.201970019}, number={4}, journal={Advanced Functional Materials}, publisher={Wiley}, author={Su, Teng and Huang, Ke and Ma, Hong and Liang, Hongxia and Dinh, Phuong-Uyen and Chen, Justin and Shen, Deliang and Allen, Tyler A. and Qiao, Li and Li, Zhenhua and et al.}, year={2019}, month={Jan}, pages={1970019} }
 @article{huang_li_su_shen_hu_cheng_2019, title={Bispecific Antibody Therapy for Effective Cardiac Repair through Redirection of Endogenous Stem Cells}, volume={2}, ISSN={["2366-3987"]}, DOI={10.1002/adtp.201900009}, abstractNote={Bone marrow stem cells (BMSCs) are a promising strategy for cardiac regenerative therapy for myocardial infarction (MI). However, cell transplantation has to overcome a number of hurdles, such as cell quality control, clinical practicality, low cell retention/engraftment, and immune reactions when allogeneic cells are used. Bispecific antibodies (BsAbs) have been developed as potential agents in cancer immunotherapy but their application is sparse in cardiovascular diseases. In the present study, BsAbs are designed by chemical cycloaddition of F(ab′)2 fragments from monoclonal anti-CD34 and anti- cardiac myosin heavy chain (CMHC) antibodies, which specifically targets circulating CD34-positive cells and injured cardiomyocytes simultaneously. It is hypothesized that intravenous administration of stem cell re-directing (SCRD) BsAbs (anti-CD34-F(ab′)2–anti-CMHC-F(ab′)2) can home endogenous BMSCs to the injured heart for cardiac repair. The in vivo studies in a mouse model with heart ischemia/reperfusion (I/R) injury demonstrate the safety and therapeutic potency of SCRD BsAb, which supports cardiac recovery by reducing scarring, promoting angiomyogenesis, and boosting cardiac function.}, number={10}, journal={ADVANCED THERAPEUTICS}, author={Huang, Ke and Li, Zhenhua and Su, Teng and Shen, Deliang and Hu, Shiqi and Cheng, Ke}, year={2019}, month={Oct} }
 @misc{liu_hu_wang_cheng_2019, title={Cell and biomaterial-based approaches to uterus regeneration}, volume={6}, ISSN={["2056-3426"]}, DOI={10.1093/rb/rbz021}, abstractNote={Asherman's syndrome (AS) is an endometrial disorder in which intrauterine adhesions crowd the uterine cavity and wall. The fibrotic adhesions are primarily the result of invasive uterine procedures that usually involve the insertion of surgical equipment into the uterus. This syndrome is accompanied by a number of clinical manifestations, including irregular or painful menstruation and infertility. The most prevalent treatment is hysteroscopy, which involves the physical removal of the fibrous strands. Within the last decade, however, the field has been exploring the use of cell-based therapeutics, in conjunction with biomaterials, to treat AS. This review is a recapitulation of the literature focused on cellular therapies for treating AS.}, number={3}, journal={REGENERATIVE BIOMATERIALS}, author={Liu, Feiran and Hu, Shiqi and Wang, Shaowei and Cheng, Ke}, year={2019}, month={Jun}, pages={141–148} }
 @misc{li_hu_cheng_2019, title={Chemical Engineering of Cell Therapy for Heart Diseases}, volume={52}, ISSN={["1520-4898"]}, DOI={10.1021/acs.accounts.9b00137}, abstractNote={Cardiovascular disease (CVD) is a major health problem worldwide. Since adult cardiomyocytes irreversibly withdraw from the cell cycle soon after birth, it is hard for cardiac cells to proliferate and regenerate after myocardial injury, such as that caused myocardial infarction (MI). Live cell-based therapies, which we term as first generation of therapeutic strategies, have been widely used for the treatment of many diseases, including CVD. However, cellular approaches have the problems of poor retention of the transplanted cells and the significant entrapment of the cells in the lungs when delivered intravenously. Another big problem is the low storage/shipping stability of live cells, which limits the manufacturability of living cell products. The field of chemical engineering focuses on designing large-scale processes to convert chemicals, raw materials, living cells, microorganisms, and energy into useful forms and products. By definition, chemical engineers conceive and design processes to produce, transform, and transport materials. This matches the direction that cell therapies are heading toward: "produce", from live cells to synthetic artificial cells; "transform", from bare cells to cell/matrix/factor combinations; and "transport". from simple systemic injections to targeted delivery. Thus, we hereby introduce the "chemical engineering of cell therapies" as a concept. In this Account, we summarize our recent efforts to develop chemical engineering approaches to repair injured hearts. To address the limitations of poor cellular retention and integration, the first step was the artificial manipulation of stem cells before injections (we term this the second generation of therapeutic strategies). For example, we took advantage of the natural infarct-targeting ability of platelet membranes by fusing them onto the surface of cardiac stromal/stem cells (CSCs). By doing so, we improved the rate at which they were delivered through the vasculature to sites of MI. In addition to modifying natural CSCs, we described a bioengineering approach that involved the encapsulation of CSCs in a polymeric microneedle patch for myocardium regeneration. The painless microneedle patches were used as an in situ delivery device, which directly transported the loaded CSCs to the MI heart. In addition to low cell retention, there are some other barriers that need to be addressed before further clinical application is viable, including the storage/shipping stability of and the evident safety concerns about live cells. Therefore, we developed the third generation of therapeutic strategies, which utilize cell-free approaches for cardiac cell therapies. Numerous studies have indicated that paracrine mechanisms reasonably explain stem cell based heart repair. By imitating or adapting natural stem cells, as well as their secretions, and using them in conjunction with biocompatible materials, we can simulate the function of natural stem cells while avoiding the complications association with the first and second generation therapeutic options. Additionally, we can develop approaches to capture endogenous stem cells and directly transport them to the infarct site. Using these third generation therapeutic strategies, we can provide unprecedented opportunities for cardiac cell therapies. We hope that our designs will promote the use of chemical engineering approaches to transform, transport, and fabricate cell-free systems as novel cardiac cell therapeutic agents for clinical applications.}, number={6}, journal={ACCOUNTS OF CHEMICAL RESEARCH}, author={Li, Zhenhua and Hu, Shiqi and Cheng, Ke}, year={2019}, month={Jun}, pages={1687–1696} }
 @misc{berry_zhu_tang_krishnamurthy_ge_cooke_chen_garry_yang_rajasekaran_et al._2019, title={Convergences of Life Sciences and Engineering in Understanding and Treating Heart Failure}, volume={124}, ISSN={["1524-4571"]}, DOI={10.1161/CIRCRESAHA.118.314216}, abstractNote={On March 1 and 2, 2018, the National Institutes of Health 2018 Progenitor Cell Translational Consortium, Cardiovascular Bioengineering Symposium, was held at the University of Alabama at Birmingham. Convergence of life sciences and engineering to advance the understanding and treatment of heart failure was the theme of the meeting. Over 150 attendees were present, and >40 scientists presented their latest work on engineering human functional myocardium for disease modeling, drug development, and heart failure research. The scientists, engineers, and physicians in the field of cardiovascular sciences met and discussed the most recent advances in their work and proposed future strategies for overcoming the major roadblocks of cardiovascular bioengineering and therapy. Particular emphasis was given for manipulation and using of stem/progenitor cells, biomaterials, and methods to provide molecular, chemical, and mechanical cues to cells to influence their identity and fate in vitro and in vivo. Collectively, these works are profoundly impacting and progressing toward deciphering the mechanisms and developing novel treatments for left ventricular dysfunction of failing hearts. Here, we present some important perspectives that emerged from this meeting.}, number={1}, journal={CIRCULATION RESEARCH}, author={Berry, Joel L. and Zhu, Wuqiang and Tang, Yao Liang and Krishnamurthy, Prasanna and Ge, Ying and Cooke, John P. and Chen, Yabing and Garry, Daniel J. and Yang, Huang-Tian and Rajasekaran, Namakkal Soorapan and et al.}, year={2019}, month={Jan}, pages={161–169} }
 @article{liu_hu_yang_li_huang_su_wang_cheng_2019, title={Hyaluronic Acid Hydrogel Integrated with Mesenchymal Stem Cell-Secretome to Treat Endometrial Injury in a Rat Model of Asherman's Syndrome}, volume={8}, ISSN={["2192-2659"]}, DOI={10.1002/adhm.201900411}, abstractNote={Stem cell therapies have made strides toward the efficacious treatment of injured endometrium and the prevention of intrauterine adhesions, or Asherman's syndrome (AS). Despite this progress, they are limited by their risk of tumor formation, low engraftment rates, as well as storage and transportation logistics. While attempts have been made to curb these issues, there remains a need for simple and effective solutions. A growing body of evidence supports the theory that delivering media, conditioned with mesenchymal stem cells, might be a promising alternative to live cell therapy. Mesenchymal stem cell-secretome (MSC-Sec) has a superior safety profile and can be stored without losing its regenerative properties. It is versatile enough to be added to a number of delivery vehicles that improve engraftment and control the release of the therapeutic. Thus, it holds great potential for the treatment of AS. Here, a new strategy for loading crosslinked hyaluronic acid gel (HA gel) with MSC-Sec is reported. The HA gel/MSC-Sec treatment paradigm creates a sustained release system that repairs endometrial injury in rats and promotes viable pregnancy.}, number={14}, journal={ADVANCED HEALTHCARE MATERIALS}, author={Liu, Feiran and Hu, Shiqi and Yang, Hua and Li, Zhenhua and Huang, Ke and Su, Teng and Wang, Shaowei and Cheng, Ke}, year={2019}, month={Jul} }
 @article{hu_li_cores_huang_su_dinh_cheng_2019, title={Needle-Free Injection of Exosomes Derived from Human Dermal Fibroblast Spheroids Ameliorates Skin Photoaging}, volume={13}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.9b04384}, abstractNote={Human dermal fibroblasts (HDFs), the main cell population of the dermis, gradually lose their ability to produce collagen and renew intercellular matrix with aging. One clinical application for the autologous trans-dermis injection of HDFs that has been approved by the Food and Drug Administration aims to refine facial contours and slow down skin aging. However, the autologous HDFs used vary in quality according to the state of patients and due to many passages they undergo during expansion. In this study, factors and exosomes derived from three-dimensional spheroids (3D HDF-XOs) and the monolayer culture of HDFs (2D HDF-XOs) were collected and compared. 3D HDF-XOs expressed a significantly higher level of tissue inhibitor of metalloproteinases-1 (TIMP-1) and differentially expressed miRNA cargos compared with 2D HDF-XOs. Next, the efficacy of 3D HDF-XOs in inducing collagen synthesis and antiaging was demonstrated in vitro and in a nude mouse photoaging model. A needle-free injector was used to administer exosome treatments. 3D HDF-XOs caused increased procollagen type I expression and a significant decrease in MMP-1 expression, mainly through the downregulation of tumor necrosis factor-alpha (TNF-α) and the upregulation of transforming growth factor beta (TGF-β). In addition, the 3D-HDF-XOs group showed a higher level of dermal collagen deposition than bone marrow mesenchymal stem cell-derived exosomes. These results indicate that exosomes from 3D cultured HDF spheroids have anti-skin-aging properties and the potential to prevent and treat cutaneous aging.}, number={10}, journal={ACS NANO}, author={Hu, Shiqi and Li, Zhenhua and Cores, Jhon and Huang, Ke and Su, Teng and Dinh, Phuong-Uyen and Cheng, Ke}, year={2019}, month={Oct}, pages={11273–11282} }
 @article{su_huang_ma_liang_dinh_chen_shen_allen_qiao_li_et al._2019, title={Platelet-Inspired Nanocells for Targeted Heart Repair After Ischemia/Reperfusion Injury}, volume={29}, ISSN={["1616-3028"]}, DOI={10.1002/adfm.201803567}, abstractNote={Cardiovascular disease is the leading cause of mortality worldwide. While reperfusion therapy is vital for patient survival post-heart attack, it also causes further tissue injury, known as myocardial ischemia/reperfusion (I/R) injury in clinical practice. Exploring ways to attenuate I/R injury is of clinical interest for improving post-ischemic recovery. A platelet-inspired nanocell (PINC) that incorporates both prostaglandin E2 (PGE2)-modified platelet membrane and cardiac stromal cell-secreted factors to target the heart after I/R injury is introduced. By taking advantage of the natural infarct-homing ability of platelet membrane and the overexpression of PGE2 receptors (EPs) in the pathological cardiac microenvironment after I/R injury, the PINCs can achieve targeted delivery of therapeutic payload to the injured heart. Furthermore, a synergistic treatment efficacy can be achieved by PINC, which combines the paracrine mechanism of cell therapy with the PGE2/EP receptor signaling that is involved in the repair and regeneration of multiple tissues. In a mouse model of myocardial I/R injury, intravenous injection of PINCs results in augmented cardiac function and mitigated heart remodeling, which is accompanied by the increase in cycling cardiomyocytes, activation of endogenous stem/progenitor cells, and promotion of angiogenesis. This approach represents a promising therapeutic delivery platform for treating I/R injury.}, number={4}, journal={ADVANCED FUNCTIONAL MATERIALS}, author={Su, Teng and Huang, Ke and Ma, Hong and Liang, Hongxia and Dinh, Phuong-Uyen and Chen, Justin and Shen, Deliang and Allen, Tyler A. and Qiao, Li and Li, Zhenhua and et al.}, year={2019}, month={Jan} }
 @article{li_feng_gao_jin_zhao_liu_yang_hu_cheng_zhang_2019, title={Porous Organic Polymer-Coated Band-Aids for Phototherapy of Bacteria-Induced Wound Infection}, volume={2}, ISSN={2576-6422 2576-6422}, url={http://dx.doi.org/10.1021/ACSABM.8B00676}, DOI={10.1021/ACSABM.8B00676}, abstractNote={Band-Aids have been widely used for wound care. For most adhesive bandages, however, they have a limited capacity to speed up the wound healing process, which in turn may cause serious wound infections. In this study, antibacterial Band-Aids, combining porphyrin-based porous organic polymers (POPs) with commercial antibiotic-free Band-Aids, are designed. Under white light irradiation, POPs can produce effective photothermal heat, as well as highly reactive oxygen species (ROS), thereby triggering the potent hyperthermia and simultaneous ROS increase on wounds. Additionally, white light is similar to sunlight, which makes POP-based Band-Aids (PBAs) ideal wound dressings for wound disinfection.}, number={2}, journal={ACS Applied Bio Materials}, publisher={American Chemical Society (ACS)}, author={Li, Zhenhua and Feng, Xiaochen and Gao, Shutao and Jin, Yan and Zhao, Wencong and Liu, Huifang and Yang, Xinjian and Hu, Shiqi and Cheng, Ke and Zhang, Jinchao}, year={2019}, month={Jan}, pages={613–618} }
 @article{qiao_hu_liu_zhang_ma_huang_li_su_vandergrif_tang_et al._2019, title={microRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potential}, volume={129}, ISSN={["1558-8238"]}, url={https://doi.org/10.1172/JCI123135}, DOI={10.1172/JCI123135}, abstractNote={Exosomes, as functional paracrine units of therapeutic cells, can partially reproduce the reparative properties of their parental cells. The constitution of exosomes, as well as their biological activity, largely depends on the cells that secrete them. We isolated exosomes from explant-derived cardiac stromal cells from patients with heart failure (FEXO) or from normal donor hearts (NEXO) and compared their regenerative activities in vitro and in vivo. Patients in the FEXO group exhibited an impaired ability to promote endothelial tube formation and cardiomyocyte proliferation in vitro. Intramyocardial injection of NEXO resulted in structural and functional improvements in a murine model of acute myocardial infarction. In contrast, FEXO therapy exacerbated cardiac function and left ventricular remodeling. microRNA array and PCR analysis revealed dysregulation of miR-21-5p in FEXO. Restoring miR-21-5p expression rescued FEXO's reparative function, whereas blunting miR-21-5p expression in NEXO diminished its therapeutic benefits. Further mechanistic studies revealed that miR-21-5p augmented Akt kinase activity through the inhibition of phosphatase and tensin homolog. Taken together, the heart failure pathological condition altered the miR cargos of cardiac-derived exosomes and impaired their regenerative activities. miR-21-5p contributes to exosome-mediated heart repair by enhancing angiogenesis and cardiomyocyte survival through the phosphatase and tensin homolog/Akt pathway.}, number={6}, journal={JOURNAL OF CLINICAL INVESTIGATION}, publisher={American Society for Clinical Investigation}, author={Qiao, Li and Hu, Shiqi and Liu, Suyun and Zhang, Hui and Ma, Hong and Huang, Ke and Li, Zhenhua and Su, Teng and Vandergrif, Adam and Tang, Junnan and et al.}, year={2019}, month={Jun}, pages={2237–2250} }
 @article{huang_hu_cheng_2018, title={A New Era of Cardiac Cell Therapy: Opportunities and Challenges}, volume={8}, ISSN={2192-2640 2192-2659}, url={http://dx.doi.org/10.1002/adhm.201801011}, DOI={10.1002/adhm.201801011}, abstractNote={Myocardial infarction (MI), caused by coronary heart disease (CHD), remains one of the most common causes of death in the United States. Over the last few decades, scientists have invested considerable resources on the study and development of cell therapies for myocardial regeneration after MI. However, due to a number of limitations, they are not yet readily available for clinical applications. Mounting evidence supports the theory that paracrine products are the main contributors to the regenerative effects attributed to these cell therapies. The next generation of cell-based MI therapies will identify and isolate cell products and derivatives, integrate them with biocompatible materials and technologies, and use them for the regeneration of damaged myocardial tissue. This review discusses the progress made thus far in pursuit of this new generation of cell therapies. Their fundamental regenerative mechanisms, their potential to combine with other therapeutic products, and their role in shaping new clinical approaches for heart tissue engineering, are addressed.}, number={2}, journal={Advanced Healthcare Materials}, publisher={Wiley}, author={Huang, Ke and Hu, Shiqi and Cheng, Ke}, year={2018}, month={Dec}, pages={1801011} }
 @misc{hu_ogle_cheng_2018, title={Body builder: from synthetic cells to engineered tissues}, volume={54}, ISSN={["1879-0410"]}, DOI={10.1016/j.ceb.2018.04.010}, abstractNote={It is estimated that 18 Americans die every day waiting for an organ donation. And even if a patient receives the organ that s/he needs, there is still >10% chance that the new organ will not work. The field of tissue engineering and regenerative medicine aims to actively use a patient's own cells, plus biomaterials and factors, to grow specific tissues for replacement or to restore normal functions of that organ, which would eliminate the need for donors and the risk of alloimmune rejection. In this review, we summarized recent advances in fabricating synthetic cells, with a specific focus on their application to cardiac regenerative medicine and tissue engineering. At the end, we pointed to challenges and future directions for the field.}, journal={CURRENT OPINION IN CELL BIOLOGY}, author={Hu, Shiqi and Ogle, Brenda M. and Cheng, Ke}, year={2018}, month={Oct}, pages={37–42} }
 @article{su_huang_daniele_hensley_young_tang_allen_vandergriff_erb_ligler_et al._2018, title={Cardiac Stem Cell Patch Integrated with Microengineered Blood Vessels Promotes Cardiomyocyte Proliferation and Neovascularization after Acute Myocardial Infarction}, volume={10}, ISSN={["1944-8252"]}, DOI={10.1021/acsami.8b13571}, abstractNote={Cardiac stem cell (CSC) therapy has shown preclinical and clinical evidence for ischemic heart repair but is limited by low cellular engraftment and survival after transplantation. Previous versions of the cardiac patch strategy improve stem cell engraftment and encourage repair of cardiac tissue. However, cardiac patches that can enhance cardiomyogenesis and angiogenesis at the injured site remain elusive. Therapies that target cardiomyocyte proliferation and new blood vessel formation hold great potential for the protection against acute myocardial infarction (MI). Here, we report a new strategy for creating a vascularized cardiac patch in a facile and modular fashion by leveraging microfluidic hydrodynamic focusing to construct the biomimetic microvessels (BMVs) that include human umbilical vein endothelial cells (HUVECs) lining the luminal surface and then encapsulating the BMVs in a fibrin gel spiked with human CSCs. We show that the endothelialized BMVs mimicked the natural architecture and function of capillaries and that the resultant vascularized cardiac patch (BMV-CSC patch) exhibited equivalent release of paracrine factors compared to those of coculture of genuine human CSCs and HUVECs after 7 days of in vitro culture. In a rat model of acute MI, the BMV-CSC patch therapy induced profound mitotic activities of cardiomyocytes in the peri-infarct region 4 weeks post-treatment. A significant increase in myocardial capillary density was noted in the infarcted hearts that received BMV-CSC patch treatment compared to the infarcted hearts treated with conventional CSC patches. The striking therapeutic benefits and the fast and facile fabrication of the BMV-CSC patch make it promising for practical applications. Our findings suggest that the BMV-CSC patch strategy may open up new possibilities for the treatment of ischemic heart injury.}, number={39}, journal={ACS APPLIED MATERIALS & INTERFACES}, author={Su, Teng and Huang, Ke and Daniele, Michael A. and Hensley, Michael Taylor and Young, Ashlyn T. and Tang, Junnan and Allen, Tyler A. and Vandergriff, Adam C. and Erb, Patrick D. and Ligler, Frances S. and et al.}, year={2018}, month={Oct}, pages={33088–33096} }
 @article{tang_wang_huang_ye_su_qiao_hensley_caranasos_zhang_gu_et al._2018, title={Cardiac cell-integrated microneedle patch for treating myocardial infarction}, volume={4}, ISSN={["2375-2548"]}, url={https://doi.org/10.1126/sciadv.aat9365}, DOI={10.1126/sciadv.aat9365}, abstractNote={A microneedle cardiac stromal cell patch has been developed for therapeutic heart regeneration after myocardial infarction.}, number={11}, journal={SCIENCE ADVANCES}, publisher={American Association for the Advancement of Science (AAAS)}, author={Tang, Junnan and Wang, Jinqiang and Huang, Ke and Ye, Yanqi and Su, Teng and Qiao, Li and Hensley, Michael Taylor and Caranasos, Thomas George and Zhang, Jinying and Gu, Zhen and et al.}, year={2018}, month={Nov} }
 @article{tang_cores_huang_cui_luo_zhang_li_qian_cheng_2018, title={Concise Review: Is Cardiac Cell Therapy Dead? Embarrassing Trial Outcomes and New Directions for the Future}, volume={7}, ISSN={2157-6564 2157-6580}, url={http://dx.doi.org/10.1002/sctm.17-0196}, DOI={10.1002/sctm.17-0196}, abstractNote={Abstract Stem cell therapy is a promising strategy for tissue regeneration. The therapeutic benefits of cell therapy are mediated by both direct and indirect mechanisms. However, the application of stem cell therapy in the clinic is hampered by several limitations. This concise review provides a brief introduction into stem cell therapies for ischemic heart disease. It summarizes cell-based and cell-free paradigms, their limitations, and the benefits of using them to target disease.}, number={4}, journal={Stem Cells Translational Medicine}, publisher={Oxford University Press (OUP)}, author={Tang, Jun-Nan and Cores, Jhon and Huang, Ke and Cui, Xiao-Lin and Luo, Lan and Zhang, Jin-Ying and Li, Tao-Sheng and Qian, Li and Cheng, Ke}, year={2018}, month={Feb}, pages={354–359} }
 @article{hu_sun_wang_ruan_zhang_ye_shen_wang_lu_cheng_et al._2018, title={Conjugation of haematopoietic stem cells and platelets decorated with anti-PD-1 antibodies augments anti-leukaemia efficacy}, volume={2}, ISSN={["2157-846X"]}, DOI={10.1038/s41551-018-0310-2}, abstractNote={Patients with acute myeloid leukaemia who relapse following therapy have few treatment options and face poor outcomes. Immune checkpoint inhibition, for example, by antibody-mediated programmed death-1 (PD-1) blockade, is a potent therapeutic modality that improves treatment outcomes in acute myeloid leukaemia. Here, we show that systemically delivered blood platelets decorated with anti-PD-1 antibodies (aPD-1) and conjugated to haematopoietic stem cells (HSCs) suppress the growth and recurrence of leukaemia in mice. Following intravenous injection into mice bearing leukaemia cells, the HSC-platelet-aPD-1 conjugate migrated to the bone marrow and locally released aPD-1, significantly enhancing anti-leukaemia immune responses, and increasing the number of active T cells, production of cytokines and chemokines, and survival time of the mice. This cellular conjugate also promoted resistance to re-challenge with leukaemia cells. Taking advantage of the homing capability of HSCs and in situ activation of platelets for the enhanced delivery of a checkpoint inhibitor, this cellular combination-mediated drug delivery strategy can significantly augment the therapeutic efficacy of checkpoint blockade.}, number={11}, journal={NATURE BIOMEDICAL ENGINEERING}, author={Hu, Quanyin and Sun, Wujin and Wang, Jinqiang and Ruan, Huitong and Zhang, Xudong and Ye, Yanqi and Shen, Song and Wang, Chao and Lu, Weiyue and Cheng, Ke and et al.}, year={2018}, month={Nov}, pages={831–840} }
 @article{liang_huang_su_li_hu_dinh_wrona_shao_qiao_vandergriff_et al._2018, title={Mesenchymal Stem Cell/Red Blood Cell-Inspired Nanoparticle Therapy in Mice with Carbon Tetrachloride-Induced Acute Liver Failure}, volume={12}, ISSN={1936-0851 1936-086X}, url={http://dx.doi.org/10.1021/ACSNANO.8B00553}, DOI={10.1021/ACSNANO.8B00553}, abstractNote={Acute liver failure is a critical condition characterized by global hepatocyte death and often time needs a liver transplantation. Such treatment is largely limited by donor organ shortage. Stem cell therapy offers a promising option to patients with acute liver failure. Yet, therapeutic efficacy and feasibility are hindered by delivery route and storage instability of live cell products. We fabricated a nanoparticle that carries the beneficial regenerative factors from mesenchymal stem cells and further coated it with the membranes of red blood cells to increase blood stability. Unlike uncoated nanoparticles, these particles promote liver cell proliferation in vitro and have lower internalization by macrophage cells. After intravenous delivery, these artificial stem cell analogs are able to remain in the liver and mitigate carbon tetrachloride-induced liver failure in a mouse model, as gauged by histology and liver function test. Our technology provides an innovative and off-the-shelf strategy to treat liver failure.}, number={7}, journal={ACS Nano}, publisher={American Chemical Society (ACS)}, author={Liang, Hongxia and Huang, Ke and Su, Teng and Li, Zhenhua and Hu, Shiqi and Dinh, Phuong-Uyen and Wrona, Emily A. and Shao, Chen and Qiao, Li and Vandergriff, Adam C. and et al.}, year={2018}, month={Jun}, pages={6536–6544} }
 @article{allen_amu_asad_cheng_2018, title={Metastatic melanoma and cervical tumor cell clusters can exit blood vessels through angiopellosis augmenting tumor formation ability}, volume={78}, ISSN={["1538-7445"]}, DOI={10.1158/1538-7445.AM2018-90}, abstractNote={Introduction Accumulating data suggests metastatic primary tumor cells can travel through the circulation and form secondary tumors as multicellular clusters. However, whether these clusters must first dissociate into single cells prior to exiting of blood vessels remains largely unknown. Of late, researchers have identified a mechanism of cell extravasation (exiting blood vessel), termed angiopellosis (Allen 2016). However, whether tumor cell clusters possess the ability to exit vessles using the angiopellosis method is unstudied. We hypothesized that circulating tumor cell (CTC) clusters could exit blood vessels while maintaining a multicellular phenotype, through angiopellosis. Methodology To test this, we used an in vivo zebrafish larvae model using the tg(fli1a:egfp) line, in which blood vessels exclusively fluoresce. First, we infused fluorescent human melanoma (A375), mouse melanoma (B16F10), and human cervical (HeLa) cells into the circulation of the larvae. Next, we used lightsheet microscopy to observe the method the tumor cells used to exit blood vessels. Additionally, mouse melanoma (B16F10) cells were intravenously infused into the circulation of C57BL/6J mice as either tumor clusters or individual cells. The mice were imaged for metastatic lung foci, to determine cluster extravasation potential. Experimental results The intravital lightsheet microscopy allowed us to determine that tumor cells can utilize angiopellosis to exit blood vessels in the zebrafish model, both as individual CTCs and CTC clusters. Extravasating CTCs exited blood vessels through angiopellosis at 94%, with only 6% exiting through the diapedesis method (n=30). CTCs which exited as a cluster through angiopellosis were observed to form tumor masses at an 88% higher rate compared to individual tumor cells in vivo, over the course of 96 hours. In the murine model, CTCs clusters which were infused via tail vein (n=4) showed significantly higher metastatic lung foci in comparison to individual CTCs that were infused (n=3). Following isolation and analysis of metastatic CTCs, multiple genes were shown to be differentially expressed in CTC clusters in both the zebrafish and murine models. Discussion Here, we show circulating tumor cell clusters possess the ability to exit blood vessels through the recently identified angiopellosis. We determined tumor cell clusters exhibit an augmented ability to proliferate in vivo, while individually tumor cells are more prone to dormancy. Our results challenge the belief that circulating tumor cell clusters must first disassociate to exit the circulation, and posits an alternative model. We propose tumor cells both travel and exit the circulation while maintaining a multicellular phenotype, using angiopellosis, stimulating proliferation-augmenting genetic/molecular alterations. This has been termed the Cancer Exodus Hypothesis. Citation Format: Tyler Allen, Emmanuel Amu, Dana Asad, Ke Cheng. Metastatic melanoma and cervical tumor cell clusters can exit blood vessels through angiopellosis augmenting tumor formation ability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 90.}, number={13}, journal={CANCER RESEARCH}, author={Allen, Tyler and Amu, Emmanuel and Asad, Dana and Cheng, Ke}, year={2018}, month={Jul} }
 @article{cui_tang_hartanto_zhang_bi_dai_qiao_cheng_zhang_2018, title={NIPAM-based Microgel Microenvironment Regulates the Therapeutic Function of Cardiac Stromal Cells}, volume={10}, ISSN={["1944-8244"]}, DOI={10.1021/acsami.8b09757}, abstractNote={To tune the chemical, physical, and mechanical microenvironment for cardiac stromal cells to treat acute myocardial infarction (MI), we prepared a series of thermally responsive microgels with different surface charges (positive, negative, and neutral) and different degrees of hydrophilicity, as well as functional groups (carboxyl, hydroxyl, amino, and methyl). These microgels were used as injectable hydrogels to create an optimized microenvironment for cardiac stromal cells (CSCs). Our results indicated that a hydrophilic and negatively charged microenvironment created from poly( N-isopropylacrylamide- co-itaconic acid) was favorable for maintaining high viability of CSCs, promoting CSC proliferation and facilitating the formation of CSC spheroids. A large number of growth factors, such as vascular endothelial growth factor (VEGF), insulin-like growth factor I (IGF-1), and stromal-derived factor-1 (SDF-1) were released from the spheroids, promoting neonatal rat cardiomyocyte activation and survival. After injecting the poly( N-isopropylacrylamide- co-itaconic acid) microgel into mice, we examined their acute inflammation and T-cell immune reactions. The microgel itself did not elicit obvious immune response. We then injected the same microgel-encapsulated with CSCs into MI mice. The result revealed the treatment-promoted MI heart repair through angiogenesis and inhibition of apoptosis with an improved cell retention rate. This study will open a door for tailoring poly( N-isopropylacrylamide)-based microgel as a delivery vehicle for CSC therapy.}, number={44}, journal={ACS APPLIED MATERIALS & INTERFACES}, author={Cui, Xiaolin and Tang, Junnan and Hartanto, Yusak and Zhang, Jiabin and Bi, Jingxiu and Dai, Sheng and Qiao, Shi Zhang and Cheng, Ke and Zhang, Hu}, year={2018}, month={Nov}, pages={37783–37796} }
 @misc{li_hu_cheng_2018, title={Platelets and their biomimetics for regenerative medicine and cancer therapies}, volume={6}, ISSN={["2050-7518"]}, DOI={10.1039/c8tb02301h}, abstractNote={In this review, we will focus on the recent progress made in the development of platelet and platelet-mimicking delivery systems for the treatment of diseases.}, number={45}, journal={JOURNAL OF MATERIALS CHEMISTRY B}, author={Li, Zhenhua and Hu, Shiqi and Cheng, Ke}, year={2018}, month={Dec}, pages={7354–7365} }
 @article{li_shen_hu_su_huang_liu_hou_cheng_2018, title={Pretargeting and Bioorthogonal Click Chemistry-Mediated Endogenous Stem Cell Homing for Heart Repair}, volume={12}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.8b05892}, abstractNote={Stem cell therapy is one of the promising strategies for the treatment of ischemic heart disease. However, the clinical application of stem cells transplantation is limited by low cell engraftment in the infarcted myocardium. Taking advantage of pretargeting and bioorthogonal chemistry, we engineered a pretargeting and bioorthogonal chemistry (PTBC) system to capture endogenous circulating stem cells and target them to the injured heart for effective repair. Two bioorthogonal antibodies were i.v. administrated with a pretargeting interval (48 h). Through bioorthogonal click reaction, the two antibodies are linked in vivo, engaging endogenous stem cells with circulating platelets. As a result, the platelets redirect the stem cells to the injured heart. In vitro and in vivo studies demonstrated that bioorthogonal click reaction was able to induce the conjugation of platelets and endothelial progenitor cells (EPCs) and enhance the binding of EPCs to collagen and injured blood vessels. More importantly, in a mouse model of acute myocardial infarction, the in vivo results of cardiac function, heart morphometry, and immunohistochemistry assessment all confirmed effective heart repair by the PTBC system.}, number={12}, journal={ACS NANO}, author={Li, Zhenhua and Shen, Deliang and Hu, Shiqi and Su, Teng and Huang, Ke and Liu, Feiran and Hou, Lei and Cheng, Ke}, year={2018}, month={Dec}, pages={12193–12200} }
 @article{mihalko_huang_sproul_cheng_brown_2018, title={Targeted Treatment of Ischemic and Fibrotic Complications of Myocardial Infarction Using a Dual-Delivery Microgel Therapeutic}, volume={12}, ISSN={1936-0851 1936-086X}, url={http://dx.doi.org/10.1021/ACSNANO.8B01977}, DOI={10.1021/ACSNANO.8B01977}, abstractNote={Myocardial infarction (MI), commonly known as a heart attack, affects millions of people worldwide and results in significant death and disabilities. A major cause of MI is fibrin-rich thrombus formation that occludes the coronary arteries, blocking blood flow to the heart and causing fibrin deposition. In treating MI, re-establishing blood flow is critical. However, ischemia reperfusion (I/R) injury itself can also occur and contributes to cardiac fibrosis. Fibrin-specific poly( N-isopropylacrylamide) nanogels (FSNs) comprised of a core-shell colloidal hydrogel architecture are utilized in this study to design a dual-delivery system that simultaneously addresses the need to (1) re-establish blood flow and (2) inhibit cardiac fibrosis following I/R injury. These therapeutic needs are met by controlling the release of a fibrinolytic protein, tissue plasminogen activator (tPA), and a small molecule cell contractility inhibitor (Y-27632). In vitro, tPA and Y-27632-loaded FSNs rapidly degrade fibrin and decrease cardiac cell stress fiber formation and connective tissue growth factor expression, which are both upregulated in cardiac fibrosis. In vivo, FSNs localize to fibrin in injured heart tissue and, when loaded with tPA and Y-27632, showed significant improvement in left ventricular ejection fraction 2 and 4 weeks post-I/R as well as significantly decreased infarct size, α-smooth muscle actin expression, and connective tissue growth factor expression 4 weeks post-I/R. Together, these data demonstrate the feasibility of this targeted therapeutic strategy to improve cardiac function following MI.}, number={8}, journal={ACS Nano}, publisher={American Chemical Society (ACS)}, author={Mihalko, Emily and Huang, Ke and Sproul, Erin and Cheng, Ke and Brown, Ashley C.}, year={2018}, month={Jul}, pages={7826–7837} }
 @article{tang_su_huang_dinh_wang_vandergriff_hensley_cores_allen_li_et al._2018, title={Targeted repair of heart injury by stem cells fused with platelet nanovesicles}, volume={2}, ISSN={["2157-846X"]}, url={https://europepmc.org/articles/PMC5976251}, DOI={10.1038/s41551-017-0182-x}, abstractNote={Stem cell transplantation, as used clinically, suffers from low retention and engraftment of the transplanted cells. Inspired by the ability of platelets to recruit stem cells to sites of injury on blood vessels, we hypothesized that platelets might enhance the vascular delivery of cardiac stem cells (CSCs) to sites of myocardial infarction injury. Here, we show that CSCs with platelet nanovesicles fused onto their surface membranes express platelet surface markers that are associated with platelet adhesion to injury sites. We also find that the modified CSCs selectively bind collagen-coated surfaces and endothelium-denuded rat aortas, and that in rat and porcine models of acute myocardial infarction the modified CSCs increase retention in the heart and reduce infarct size. Platelet-nanovesicle-fused CSCs thus possess the natural targeting and repairing ability of their parental cell types. This stem cell manipulation approach is fast, straightforward and safe, does not require genetic alteration of the cells, and should be generalizable to multiple cell types.}, number={1}, journal={NATURE BIOMEDICAL ENGINEERING}, author={Tang, Junnan and Su, Teng and Huang, Ke and Dinh, Phuong-Uyen and Wang, Zegen and Vandergriff, Adam and Hensley, Michael T. and Cores, Jhon and Allen, Tyler and Li, Taosheng and et al.}, year={2018}, month={Jan}, pages={17–26} }
 @article{vandergriff_huang_shen_hu_hensley_caranasos_qian_cheng_2018, title={Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide}, volume={8}, ISSN={["1838-7640"]}, DOI={10.7150/thno.20524}, abstractNote={Rationale: Cardiac stem cell-derived exosomes have been demonstrated to promote cardiac regeneration following myocardial infarction in preclinical studies. Recent studies have used intramyocardial injection in order to concentrate exosomes in the infarct. Though effective in a research setting, this method is not clinically appealing due to its invasive nature. We propose the use of a targeting peptide, cardiac homing peptide (CHP), to target intravenously-infused exosomes to the infarcted heart. Methods: Exosomes were conjugated with CHP through a DOPE-NHS linker. Ex vivo targeting was analyzed by incubating organ sections with the CHP exosomes and analyzing with fluorescence microscopy. In vitro assays were performed on neonatal rat cardiomyocytes and H9C2 cells. For the animal study, we utilized an ischemia/reperfusion rat model. Animals were treated with either saline, scramble peptide exosomes, or CHP exosomes 24 h after surgery. Echocardiography was performed 4 h after surgery and 21 d after surgery. At 21 d, animals were sacrificed, and organs were collected for analysis. Results: By conjugating the exosomes with CHP, we demonstrate increased retention of the exosomes within heart sections ex vivo and in vitro with neonatal rat cardiomyocytes. In vitro studies showed improved viability, reduced apoptosis and increased exosome uptake when using CHP-XOs. Using an animal model of ischemia/reperfusion injury, we measured the heart function, infarct size, cellular proliferation, and angiogenesis, with improved outcomes with the CHP exosomes. Conclusions: Our results demonstrate a novel method for increasing delivery of for treatment of myocardial infarction. By targeting exosomes to the infarcted heart, there was a significant improvement in outcomes with reduced fibrosis and scar size, and increased cellular proliferation and angiogenesis.}, number={7}, journal={THERANOSTICS}, author={Vandergriff, Adam and Huang, Ke and Shen, Deliang and Hu, Shiqi and Hensley, Michael Taylor and Caranasos, Thomas G. and Qian, Li and Cheng, Ke}, year={2018}, pages={1869–1878} }
 @article{tang_vandergriff_wang_hensley_cores_allen_dinh_zhang_caranasos_cheng_2017, title={A Regenerative Cardiac Patch Formed by Spray Painting of Biomaterials onto the Heart}, volume={23}, ISSN={1937-3384 1937-3392}, url={http://dx.doi.org/10.1089/ten.TEC.2016.0492}, DOI={10.1089/ten.tec.2016.0492}, abstractNote={Layering a regenerative polymer scaffold on the surface of the heart, termed as a cardiac patch, has been proven to be effective in preserving cardiac function after myocardial infarction (MI). However, the placement of such a patch on the heart usually needs open-chest surgery, which is traumatic, therefore prevents the translation of this strategy into the clinic. We sought to device a way to apply a cardiac patch by spray painting in situ polymerizable biomaterials onto the heart with a minimally invasive procedure. To prove the concept, we used platelet fibrin gel as the "paint" material in a mouse model of MI. The use of the spraying system allowed for placement of a uniform cardiac patch on the heart in a mini-invasive manner without the need for sutures or glue. The spray treatment promoted cardiac repair and attenuated cardiac dysfunction after MI.}, number={3}, journal={Tissue Engineering Part C: Methods}, publisher={Mary Ann Liebert Inc}, author={Tang, Junnan and Vandergriff, Adam and Wang, Zegen and Hensley, Michael Taylor and Cores, Jhon and Allen, Tyler A. and Dinh, Phuong-Uyen and Zhang, Jinying and Caranasos, Thomas George and Cheng, Ke}, year={2017}, month={Mar}, pages={146–155} }
 @article{dinh_cores_hensley_vandergriff_tang_allen_caranasos_adler_lobo_cheng_2017, title={Derivation of therapeutic lung spheroid cells from minimally invasive transbronchial pulmonary biopsies}, volume={18}, ISSN={1465-993X}, url={http://dx.doi.org/10.1186/s12931-017-0611-0}, DOI={10.1186/s12931-017-0611-0}, abstractNote={Resident stem and progenitor cells have been identified in the lung over the last decade, but isolation and culture of these cells remains a challenge. Thus, although these lung stem and progenitor cells provide an ideal source for stem-cell based therapy, mesenchymal stem cells (MSCs) remain the most popular cell therapy product for the treatment of lung diseases. Surgical lung biopsies can be the tissue source but such procedures carry a high risk of mortality.In this study we demonstrate that therapeutic lung cells, termed "lung spheroid cells" (LSCs) can be generated from minimally invasive transbronchial lung biopsies using a three-dimensional culture technique. The cells were then characterized by flow cytometry and immunohistochemistry. Angiogenic potential was tested by in-vitro HUVEC tube formation assay. In-vivo bio- distribution of LSCs was examined in athymic nude mice after intravenous delivery.From one lung biopsy, we are able to derive >50 million LSC cells at Passage 2. These cells were characterized by flow cytometry and immunohistochemistry and were shown to represent a mixture of lung stem cells and supporting cells. When introduced systemically into nude mice, LSCs were retained primarily in the lungs for up to 21 days.Here, for the first time, we demonstrated that direct culture and expansion of human lung progenitor cells from pulmonary tissues, acquired through a minimally invasive biopsy, is possible and straightforward with a three-dimensional culture technique. These cells could be utilized in long-term expansion of lung progenitor cells and as part of the development of cell-based therapies for the treatment of lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).}, number={1}, journal={Respiratory Research}, publisher={Springer Nature}, author={Dinh, Phuong-Uyen C. and Cores, Jhon and Hensley, M. Taylor and Vandergriff, Adam C. and Tang, Junnan and Allen, Tyler A. and Caranasos, Thomas G. and Adler, Kenneth B. and Lobo, Leonard J. and Cheng, Ke}, year={2017}, month={Jun} }
 @article{luo_tang_nishi_yan_dinh_cores_kudo_zhang_li_cheng_2017, title={Fabrication of Synthetic Mesenchymal Stem Cells for the Treatment of Acute Myocardial Infarction in Mice}, volume={120}, ISSN={0009-7330 1524-4571}, url={http://dx.doi.org/10.1161/CIRCRESAHA.116.310374}, DOI={10.1161/circresaha.116.310374}, abstractNote={Rationale: Stem cell therapy faces several challenges. It is difficult to grow, preserve, and transport stem cells before they are administered to the patient. Synthetic analogs for stem cells represent a new approach to overcome these hurdles and hold the potential to revolutionize regenerative medicine. Objective: We aim to fabricate synthetic analogs of stem cells and test their therapeutic potential for treatment of acute myocardial infarction in mice. Methods and Results: We packaged secreted factors from human bone marrow–derived mesenchymal stem cells (MSC) into poly(lactic-co-glycolic acid) microparticles and then coated them with MSC membranes. We named these therapeutic particles synthetic MSC (or synMSC). synMSC exhibited a factor release profile and surface antigens similar to those of genuine MSC. synMSC promoted cardiomyocyte functions and displayed cryopreservation and lyophilization stability in vitro and in vivo. In a mouse model of acute myocardial infarction, direct injection of synMSC promoted angiogenesis and mitigated left ventricle remodeling. Conclusions: We successfully fabricated a synMSC therapeutic particle and demonstrated its regenerative potential in mice with acute myocardial infarction. The synMSC strategy may provide novel insight into tissue engineering for treating multiple diseases.}, number={11}, journal={Circulation Research}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Luo, Lan and Tang, Junnan and Nishi, Kodai and Yan, Chen and Dinh, Phuong-Uyen and Cores, Jhon and Kudo, Takashi and Zhang, Jinying and Li, Tao-Sheng and Cheng, Ke}, year={2017}, month={May}, pages={1768–1775} }
 @article{tang_cui_caranasos_hensley_vandergriff_hartanto_shen_zhang_zhang_cheng_2017, title={Heart Repair Using Nanogel-Encapsulated Human Cardiac Stem Cells in Mice and Pigs with Myocardial Infarction}, volume={11}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.7b01008}, abstractNote={Stem cell transplantation is currently implemented clinically but is limited by low retention and engraftment of transplanted cells and the adverse effects of inflammation and immunoreaction when allogeneic or xenogeneic cells are used. Here, we demonstrate the safety and efficacy of encapsulating human cardiac stem cells (hCSCs) in thermosensitive poly(N-isopropylacrylamine-co-acrylic acid) or P(NIPAM-AA) nanogel in mouse and pig models of myocardial infarction (MI). Unlike xenogeneic hCSCs injected in saline, injection of nanogel-encapsulated hCSCs does not elicit systemic inflammation or local T cell infiltrations in immunocompetent mice. In mice and pigs with acute MI, injection of encapsulated hCSCs preserves cardiac function and reduces scar sizes, whereas injection of hCSCs in saline has an adverse effect on heart healing. In conclusion, thermosensitive nanogels can be used as a stem cell carrier: the porous and convoluted inner structure allows nutrient, oxygen, and secretion diffusion but can prevent the stem cells from being attacked by immune cells.}, number={10}, journal={ACS NANO}, author={Tang, Junnan and Cui, Xiaolin and Caranasos, Thomas G. and Hensley, M. Taylor and Vandergriff, Adam C. and Hartanto, Yusak and Shen, Deliang and Zhang, Hu and Zhang, Jinying and Cheng, Ke}, year={2017}, month={Oct}, pages={9738–9749} }
 @article{hensley_tang_woodruff_defrancesco_tou_williams_breen_meurs_keene_cheng_et al._2017, title={Intracoronary allogeneic cardiosphere-derived stem cells are safe for use in dogs with dilated cardiomyopathy}, volume={21}, ISSN={1582-1838}, url={http://dx.doi.org/10.1111/jcmm.13077}, DOI={10.1111/jcmm.13077}, abstractNote={Cardiosphere-derived cells (CDCs) have been shown to reduce scar size and increase viable myocardium in human patients with mild/moderate myocardial infarction. Studies in rodent models suggest that CDC therapy may confer therapeutic benefits in patients with non-ischaemic dilated cardiomyopathy (DCM). We sought to determine the safety and efficacy of allogeneic CDC in a large animal (canine) model of spontaneous DCM. Canine CDCs (cCDCs) were grown from a donor dog heart. Similar to human CDCs, cCDCs express CD105 and are slightly positive for c-kit and CD90. Thirty million of allogeneic cCDCs was infused into the coronary vessels of Doberman pinscher dogs with spontaneous DCM. Adverse events were closely monitored, and cardiac functions were measured by echocardiography. No adverse events occurred during and after cell infusion. Histology on dog hearts (after natural death) revealed no sign of immune rejection from the transplanted cells.}, number={8}, journal={Journal of Cellular and Molecular Medicine}, publisher={Wiley}, author={Hensley, Michael Taylor and Tang, Junnan and Woodruff, Kathleen and Defrancesco, Teresa and Tou, Sandra and Williams, Christina M. and Breen, Mathew and Meurs, Kathryn and Keene, Bruce and Cheng, Ke and et al.}, year={2017}, month={Mar}, pages={1503–1512} }
 @article{fagg_liu_yang_cheng_chung_kim_wu_fair_2017, title={Magnetic Targeting of Stem Cell Derivatives Enhances Hepatic Engraftment into Structurally Normal Liver}, volume={26}, ISSN={0963-6897 1555-3892}, url={http://dx.doi.org/10.1177/0963689717737320}, DOI={10.1177/0963689717737320}, abstractNote={Attaining consistent robust engraftment in the structurally normal liver is an obstacle for cellular transplantation. Most experimental approaches to increase transplanted cells’ engraftment involve recipient-centered deleterious methods such as partial hepatectomy or irradiation which may be unsuitable in the clinic. Here, we present a cell-based strategy that increases engraftment into the structurally normal liver using a combination of magnetic targeting and proliferative endoderm progenitor (EPs) cells. Magnetic labeling has little effect on cell viability and differentiation, but in the presence of magnetic targeting, it increases the initial dwell time of transplanted EPs into the undamaged liver parenchyma. Consequently, greater cell retention in the liver is observed concomitantly with fewer transplanted cells in the lungs. These highly proliferative cells then significantly increase their biomass over time in the liver parenchyma, approaching nearly 4% of total liver cells 30 d after transplant. Therefore, the cell-based mechanisms of increased initial dwell time through magnetic targeting combined with high rate of proliferation in situ yield significant engraftment in the undamaged liver.}, number={12}, journal={Cell Transplantation}, publisher={SAGE Publications}, author={Fagg, W. Samuel and Liu, Naiyou and Yang, Ming-Jim and Cheng, Ke and Chung, Eric and Kim, Jae-Sung and Wu, Gordon and Fair, Jeffrey}, year={2017}, month={Dec}, pages={1868–1877} }
 @article{cores_hensley_kinlaw_rikard_dinh_paudel_tang_vandergriff_allen_li_et al._2017, title={Safety and Efficacy of Allogeneic Lung Spheroid Cells in a Mismatched Rat Model of Pulmonary Fibrosis}, volume={6}, ISSN={2157-6564}, url={http://dx.doi.org/10.1002/sctm.16-0374}, DOI={10.1002/sctm.16-0374}, abstractNote={Abstract Idiopathic pulmonary fibrosis is a devastating interstitial lung disease characterized by the relentless deposition of extracellular matrix causing lung distortions and dysfunctions. The prognosis after detection is merely 3–5 years and the only two Food and Drug Administration-approved drugs treat the symptoms, not the disease, and have numerous side effects. Stem cell therapy is a promising treatment strategy for pulmonary fibrosis. Current animal and clinical studies focus on the use of adipose or bone marrow-derived mesenchymal stem cells. We, instead, have established adult lung spheroid cells (LSCs) as an intrinsic source of therapeutic lung stem cells. In the present study, we compared the efficacy and safety of syngeneic and allogeneic LSCs in immuno-competent rats with bleomycin-induced pulmonary inflammation in an effort to mitigate fibrosis development. We found that infusion of allogeneic LSCs reduces the progression of inflammation and fibrotic manifestation and preserves epithelial and endothelial health without eliciting significant immune rejection. Our study sheds light on potential future developments of LSCs as an allogeneic cell therapy for humans with pulmonary fibrosis.}, number={10}, journal={STEM CELLS Translational Medicine}, publisher={Wiley}, author={Cores, Jhon and Hensley, M. Taylor and Kinlaw, Kathryn and Rikard, S. Michaela and Dinh, Phuong-Uyen and Paudel, Dipti and Tang, Junnan and Vandergriff, Adam C. and Allen, Tyler A. and Li, Yazhou and et al.}, year={2017}, month={Aug}, pages={1905–1916} }
 @article{tang_shen_caranasos_wang_vandergriff_allen_hensley_dinh_cores_li_et al._2017, title={Therapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome}, volume={8}, ISSN={2041-1723}, url={http://dx.doi.org/10.1038/ncomms13724}, DOI={10.1038/ncomms13724}, abstractNote={Stem cell therapy represents a promising strategy in regenerative medicine. However, cells need to be carefully preserved and processed before usage. In addition, cell transplantation carries immunogenicity and/or tumourigenicity risks. Mounting lines of evidence indicate that stem cells exert their beneficial effects mainly through secretion (of regenerative factors) and membrane-based cell-cell interaction with the injured cells. Here, we fabricate a synthetic cell-mimicking microparticle (CMMP) that recapitulates stem cell functions in tissue repair. CMMPs carry similar secreted proteins and membranes as genuine cardiac stem cells do. In a mouse model of myocardial infarction, injection of CMMPs leads to the preservation of viable myocardium and augmentation of cardiac functions similar to cardiac stem cell therapy. CMMPs (derived from human cells) do not stimulate T-cell infiltration in immuno-competent mice. In conclusion, CMMPs act as 'synthetic stem cells' which mimic the paracrine and biointerfacing activities of natural stem cells in therapeutic cardiac regeneration.}, number={1}, journal={Nature Communications}, publisher={Springer Science and Business Media LLC}, author={Tang, Junnan and Shen, Deliang and Caranasos, Thomas George and Wang, Zegen and Vandergriff, Adam C. and Allen, Tyler A. and Hensley, Michael Taylor and Dinh, Phuong-Uyen and Cores, Jhon and Li, Tao-Sheng and et al.}, year={2017}, month={Jan} }
 @article{wang_dong_niu_zhang_zhang_liu_zhou_wu_cheng_2017, title={Transplantation of human villous trophoblasts preserves cardiac function in mice with acute myocardial infarction}, volume={21}, ISSN={["1582-4934"]}, DOI={10.1111/jcmm.13165}, abstractNote={Over the past decade, cell therapies have provided promising strategies for the treatment of ischaemic cardiomyopathy. Particularly, the beneficial effects of stem cells, including bone marrow stem cells (BMSCs), endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs), have been demonstrated by substantial preclinical and clinical studies. Nevertheless stem cell therapy is not always safe and effective. Hence, there is an urgent need for alternative sources of cells to promote cardiac regeneration. Human villous trophoblasts (HVTs) play key roles in embryonic implantation and placentation. In this study, we show that HVTs can promote tube formation of human umbilical vein endothelial cells (HUVECs) on Matrigel and enhance the resistance of neonatal rat cardiomyocytes (NRCMs) to oxidative stress in vitro. Delivery of HVTs to ischaemic area of heart preserved cardiac function and reduced fibrosis in a mouse model of acute myocardial infarction (AMI). Histological analysis revealed that transplantation of HVTs promoted angiogenesis in AMI mouse hearts. In addition, our data indicate that HVTs exert their therapeutic benefit through paracrine mechanisms. Meanwhile, injection of HVTs to mouse hearts did not elicit severe immune response. Taken together, our study demonstrates HVT may be used as a source for cell therapy or a tool to study cell-derived soluble factors for AMI treatment.}, number={10}, journal={JOURNAL OF CELLULAR AND MOLECULAR MEDICINE}, author={Wang, Zegen and Dong, Ningzheng and Niu, Yayan and Zhang, Zhiwei and Zhang, Ce and Liu, Meng and Zhou, Tiantian and Wu, Qingyu and Cheng, Ke}, year={2017}, month={Oct}, pages={2432–2440} }
 @article{allen_gracieux_talib_tokarz_hensley_cores_vandergriff_tang_de andrade_dinh_et al._2016, title={Angiopellosis as an Alternative Mechanism of Cell Extravasation}, volume={35}, ISSN={1066-5099}, url={http://dx.doi.org/10.1002/stem.2451}, DOI={10.1002/stem.2451}, abstractNote={Abstract Stem cells possess the ability to home in and travel to damaged tissue when injected intravenously. For the cells to exert their therapeutic effect, they must cross the blood vessel wall and enter the surrounding tissues. The mechanism of extravasation injected stem cells employ for exit has yet to be characterized. Using intravital microscopy and a transgenic zebrafish line Tg(fli1a:egpf) with GFP-expressing vasculature, we documented the detailed extravasation processes in vivo for injected stem cells in comparison to white blood cells (WBCs). While WBCs left the blood vessels by the standard diapedesis process, injected cardiac and mesenchymal stem cells underwent a distinct method of extravasation that was markedly different from diapedesis. Here, the vascular wall undergoes an extensive remodeling to allow the cell to exit the lumen, while the injected cell remains distinctively passive in activity. We termed this process Angio-pello-sis, which represents an alternative mechanism of cell extravasation to the prevailing theory of diapedesis. Video Highlight: https://youtu.be/i5EI-ZvhBps}, number={1}, journal={STEM CELLS}, publisher={Wiley}, author={Allen, Tyler A. and Gracieux, David and Talib, Maliha and Tokarz, Debra A. and Hensley, M. Taylor and Cores, Jhon and Vandergriff, Adam and Tang, Junnan and de Andrade, James B.M. and Dinh, Phuong-Uyen and et al.}, year={2016}, month={Jul}, pages={170–180} }
 @article{shen_tang_hensley_li_caranasos_zhang_zhang_cheng_2016, title={Effects of Matrix Metalloproteinases on the Performance of Platelet Fibrin Gel Spiked With Cardiac Stem Cells in Heart Repair}, volume={5}, ISSN={["2157-6580"]}, DOI={10.5966/sctm.2015-0194}, abstractNote={Abstract Stem cells and biomaterials have been studied for therapeutic cardiac repair. Previous studies have shown the beneficial effects of platelet fibrin gel and cardiac stem cells when cotransplanted into rodent hearts with myocardial infarction (MI). We hypothesized that matrix metalloproteinases (MMPs) play an important role in such protection. Thus, the present study is designed to elucidate the effects of MMP inhibition on the therapeutic benefits of intramyocardial injection of platelet fibrin gel spiked with cardiac stem cells (cell-gel) in a rat model of acute MI. In vitro, broad-spectrum MMP inhibitor GM6001 undermines cell spreading and cardiomyocyte contraction. In a syngeneic rat model of myocardial infarction, MMP inhibition blunted the recruitment of endogenous cardiovascular cells into the injected biomaterials, therefore hindering de novo angiogenesis and cardiomyogenesis. Echocardiography and histology 3 weeks after treatment revealed that metalloproteinase inhibition diminished the functional and structural benefits of cell-gel in treating MI. Reduction of host angiogenesis, cardiomyocyte cycling, and MMP-2 activities was evident in animals treated with GM6001. Our findings suggest that MMPs play a critical role in the therapeutic benefits of platelet fibrin gel spiked with cardiac stem cells for treating MI. Significance In this study, the effects of matrix metalloproteinase inhibition on the performance of platelet gel spiked with cardiac stem cells (cell-gel) for heart regeneration are explored. The results demonstrate that matrix metalloproteinases are required for cell-gel to exert its benefits in cardiac repair. Inhibition of matrix metalloproteinases reduces cell engraftment, host angiogenesis, and recruitment of endogenous cardiovascular cells in rats with heart attack.}, number={6}, journal={STEM CELLS TRANSLATIONAL MEDICINE}, author={Shen, Deliang and Tang, Junnan and Hensley, Michael Taylor and Li, Taosheng and Caranasos, Thomas George and Zhang, Tianxia and Zhang, Jinying and Cheng, Ke}, year={2016}, month={Jun}, pages={793–803} }
 @article{henry_cores_hensley_anthony_vandergriff_andrade_allen_caranasos_lobo_cheng_2015, title={Adult Lung Spheroid Cells Contain Progenitor Cells and Mediate Regeneration in Rodents With Bleomycin-Induced Pulmonary Fibrosis}, volume={4}, ISSN={["2157-6580"]}, DOI={10.5966/sctm.2015-0062}, abstractNote={Abstract Lung diseases are devastating conditions and ranked as one of the top five causes of mortality worldwide according to the World Health Organization. Stem cell therapy is a promising strategy for lung regeneration. Previous animal and clinical studies have focused on the use of mesenchymal stem cells (from other parts of the body) for lung regenerative therapies. We report a rapid and robust method to generate therapeutic resident lung progenitors from adult lung tissues. Outgrowth cells from healthy lung tissue explants are self-aggregated into three-dimensional lung spheroids in a suspension culture. Without antigenic sorting, the lung spheroids recapitulate the stem cell niche and contain a natural mixture of lung stem cells and supporting cells. In vitro, lung spheroid cells can be expanded to a large quantity and can form alveoli-like structures and acquire mature lung epithelial phenotypes. In severe combined immunodeficiency mice with bleomycin-induced pulmonary fibrosis, intravenous injection of human lung spheroid cells inhibited apoptosis, fibrosis, and infiltration but promoted angiogenesis. In a syngeneic rat model of pulmonary fibrosis, lung spheroid cells outperformed adipose-derived mesenchymal stem cells in reducing fibrotic thickening and infiltration. Previously, lung spheroid cells (the spheroid model) had only been used to study lung cancer cells. Our data suggest that lung spheroids and lung spheroid cells from healthy lung tissues are excellent sources of regenerative lung cells for therapeutic lung regeneration. Significance The results from the present study will lead to future human clinical trials using lung stem cell therapies to treat various incurable lung diseases, including pulmonary fibrosis. The data presented here also provide fundamental knowledge regarding how injected stem cells mediate lung repair in pulmonary fibrosis.}, number={11}, journal={STEM CELLS TRANSLATIONAL MEDICINE}, author={Henry, Eric and Cores, Jhon and Hensley, M. Taylor and Anthony, Shirena and Vandergriff, Adam and Andrade, James B. M. and Allen, Tyler and Caranasos, Thomas G. and Lobo, Leonard J. and Cheng, Ke}, year={2015}, month={Nov}, pages={1265–1274} }
 @article{hensley_andrade_keene_meurs_tang_wang_caranasos_piedrahita_li_cheng_et al._2015, title={Cardiac regenerative potential of cardiosphere-derived cells from adult dog hearts}, volume={19}, ISSN={1582-1838}, url={http://dx.doi.org/10.1111/jcmm.12585}, DOI={10.1111/jcmm.12585}, abstractNote={The regenerative potential of cardiosphere-derived cells (CDCs) for ischaemic heart disease has been demonstrated in mice, rats, pigs and a recently completed clinical trial. The regenerative potential of CDCs from dog hearts has yet to be tested. Here, we show that canine CDCs can be produced from adult dog hearts. These cells display similar phenotypes in comparison to previously studied CDCs derived from rodents and human beings. Canine CDCs can differentiate into cardiomyocytes, smooth muscle cells and endothelial cells in vitro. In addition, conditioned media from canine CDCs promote angiogenesis but inhibit cardiomyocyte death. In a doxorubicin-induced mouse model of dilated cardiomyopathy (DCM), intravenous infusion of canine CDCs improves cardiac function and decreases cardiac fibrosis. Histology revealed that injected canine CDCs engraft in the mouse heart and increase capillary density. Out study demonstrates the regenerative potential of canine CDCs in a mouse model of DCM.}, number={8}, journal={Journal of Cellular and Molecular Medicine}, publisher={Wiley}, author={Hensley, M. T. and Andrade, J. and Keene, B. and Meurs, Kathryn and Tang, J. N. and Wang, Z. G. and Caranasos, T. G. and Piedrahita, J. and Li, T. S. and Cheng, K. and et al.}, year={2015}, month={Apr}, pages={1805–1813} }
 @article{kanazawa_tseliou_malliaras_yee_dawkins_de couto_smith_kreke_seinfeld_middleton_et al._2015, title={Cellular Postconditioning Allogeneic Cardiosphere-Derived Cells Reduce Infarct Size and Attenuate Microvascular Obstruction When Administered After Reperfusion in Pigs With Acute Myocardial Infarction}, volume={8}, ISSN={["1941-3297"]}, DOI={10.1161/circheartfailure.114.001484}, abstractNote={Background— Intracoronary delivery of cardiosphere-derived cells (CDCs) has been demonstrated to be safe and effective in porcine and human chronic myocardial infarction. However, intracoronary delivery of CDCs after reperfusion in acute myocardial infarction has never been assessed in a clinically-relevant large animal model. We tested CDCs as adjunctive therapy to reperfusion in a porcine model of myocardial infarction. Methods and Results— First, escalating doses (5, 7.5, and 10 million cells) of allogeneic CDCs were administered intracoronary 30 minutes after reperfusion. Forty-eight hours later, left ventriculography was performed and animals euthanized to measure area at risk, infarct size (IS), and microvascular obstruction. Second, identical end points were measured in a pivotal study of minipigs (n=14) that received 8.5 to 9 million allogeneic CDCs, placebo solution, or sham. Multiple indicators of cardioprotection were observed with 7.5 and 10 million allogeneic CDCs, but not 5 million CDCs, relative to control. In the pivotal study, IS, microvascular obstruction, cardiomyocyte apoptosis, and adverse left ventricular remodeling were all smaller in the CDC group than in sham or placebo groups. In addition, serum troponin I level at 24 hours was lower after CDC infusion than that in the placebo or sham groups, consistent with the histologically-demonstrated reduction in IS. Conclusions— Intracoronary delivery of allogeneic CDCs is safe, feasible, and effective in cardioprotection, reducing IS, preventing microvascular obstruction, and attenuating adverse acute remodeling. This novel cardioprotective effect, which we call cellular postconditioning, differs from previous strategies to reduce IS in that it works even when initiated with significant delay after reflow.}, number={2}, journal={CIRCULATION-HEART FAILURE}, author={Kanazawa, Hideaki and Tseliou, Eleni and Malliaras, Konstantinos and Yee, Kristine and Dawkins, James F. and De Couto, Geoffrey and Smith, Rachel R. and Kreke, Michelle and Seinfeld, Jeffrey and Middleton, Ryan C. and et al.}, year={2015}, month={Mar}, pages={322–332} }
 @inbook{vandergriff_hensley_cheng_2015, title={Cryopreservation of Neonatal Cardiomyocytes}, volume={1299}, ISBN={9781493925711 9781493925728}, ISSN={1064-3745 1940-6029}, url={http://dx.doi.org/10.1007/978-1-4939-2572-8_12}, DOI={10.1007/978-1-4939-2572-8_12}, booktitle={Methods in Molecular Biology}, publisher={Springer New York}, author={Vandergriff, Adam C. and Hensley, M. Taylor and Cheng, Ke}, year={2015}, pages={153–160} }
 @article{vandergriff_de andrade_tang_hensley_piedrahita_caranasos_cheng_2015, title={Intravenous Cardiac Stem Cell-Derived Exosomes Ameliorate Cardiac Dysfunction in Doxorubicin Induced Dilated Cardiomyopathy}, volume={2015}, ISSN={1687-966X 1687-9678}, url={http://dx.doi.org/10.1155/2015/960926}, DOI={10.1155/2015/960926}, abstractNote={Despite the efficacy of cardiac stem cells (CSCs) for treatment of cardiomyopathies, there are many limitations to stem cell therapies. CSC-derived exosomes (CSC-XOs) have been shown to be responsible for a large portion of the regenerative effects of CSCs. Using a mouse model of doxorubicin induced dilated cardiomyopathy, we study the effects of systemic delivery of human CSC-XOs in mice. Mice receiving CSC-XOs showed improved heart function via echocardiography, as well as decreased apoptosis and fibrosis. In spite of using immunocompetent mice and human CSC-XOs, mice showed no adverse immune reaction. The use of CSC-XOs holds promise for overcoming the limitations of stem cells and improving cardiac therapies.}, journal={Stem Cells International}, publisher={Hindawi Limited}, author={Vandergriff, Adam C. and de Andrade, James Bizetto Meira and Tang, Junnan and Hensley, M. Taylor and Piedrahita, Jorge A. and Caranasos, Thomas G. and Cheng, Ke}, year={2015}, pages={1–8} }
 @article{vandergriff_hensley_cheng_2015, title={Isolation and Cryopreservation of Neonatal Rat Cardiomyocytes}, ISSN={1940-087X}, url={http://dx.doi.org/10.3791/52726}, DOI={10.3791/52726}, abstractNote={Cell culture has become increasingly important in cardiac research, but due to the limited proliferation of cardiomyocytes, culturing cardiomyocytes is difficult and time consuming. The most commonly used cells are neonatal rat cardiomyocytes (NRCMs), which require isolation every time cells are needed. The birth of the rats can be unpredictable. Cryopreservation is proposed to allow for cells to be stored until needed, yet freezing/thawing methods for primary cardiomyocytes are challenging due to the sensitivity of the cells. Using the proper cryoprotectant, dimethyl sulfoxide (DMSO), cryopreservation was achieved. By slowly extracting the DMSO while thawing the cells, cultures were obtained with viable NRCMs. NRCM phenotype was verified using immunocytochemistry staining for α-sarcomeric actinin. In addition, cells also showed spontaneous contraction after several days in culture. Cell viability after thawing was acceptable at 40-60%. In spite of this, the methods outlined allow one to easily cryopreserve and thaw NRCMs. This gives researchers a greater amount of flexibility in planning experiments as well as reducing the use of animals.}, number={98}, journal={Journal of Visualized Experiments}, publisher={MyJove Corporation}, author={Vandergriff, Adam C. and Hensley, Michael Taylor and Cheng, Ke}, year={2015}, month={Apr} }
 @article{andrade_tang_hensley_vandergriff_cores_henry_allen_caranasos_wang_zhang_et al._2015, title={Rapid and Efficient Production of Coronary Artery Ligation and Myocardial Infarction in Mice Using Surgical Clips}, volume={10}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0143221}, abstractNote={The coronary artery ligation model in rodents mimics human myocardial infarction (MI). Normally mechanical ventilation and prolonged anesthesia period are needed. Recently, a method has been developed to create MI by popping-out the heart (without ventilation) followed by immediate suture ligation. Mortality is high due to the time-consuming suture ligation process while the heart is exposed. We sought to improve this method and reduce mortality by rapid coronary ligation using a surgical clip instead of a suture.Mice were randomized into 3 groups: clip MI (CMI), suture MI (SMI), or sham (SHAM). In all groups, heart was manually exposed without intubation through a small incision on the chest wall. Unlike the conventional SMI method, mice in the CMI group received a metal clip on left anterior descending artery (LAD), quickly dispensed by an AutoSuture Surgiclip™. The CMI method took only 1/3 of ligation time of the standard SMI method and improved post-MI survival rate. TTC staining and Masson's trichrome staining revealed a similar degree of infarct size in the SMI and CMI groups. Echocardiograph confirmed that both SMI and CMI groups had a similar reduction of ejection fraction and fraction shortening over the time. Histological analysis showed that the numbers of CD68+ macrophages and apoptotic cells (TUNEL-positive) are indistinguishable between the two groups.This new method, taking only less than 3 minutes to complete, represents an efficient myocardial infarction model in rodents.}, number={11}, journal={PLOS ONE}, author={Andrade, James N. B. M. and Tang, Junnan and Hensley, Michael Taylor and Vandergriff, Adam and Cores, Jhon and Henry, Eric and Allen, Tyler A. and Caranasos, Thomas George and Wang, Zegen and Zhang, Tianxia and et al.}, year={2015}, month={Nov} }
 @article{yee_malliaras_kanazawa_tseliou_cheng_luthringer_ho_takayama_minamino_dawkins_et al._2014, title={Allogeneic Cardiospheres Delivered via Percutaneous Transendocardial Injection Increase Viable Myocardium, Decrease Scar Size, and Attenuate Cardiac Dilatation in Porcine Ischemic Cardiomyopathy}, volume={9}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0113805}, abstractNote={Epicardial injection of heart-derived cell products is safe and effective post-myocardial infarction (MI), but clinically-translatable transendocardial injection has never been evaluated. We sought to assess the feasibility, safety and efficacy of percutaneous transendocardial injection of heart-derived cells in porcine chronic ischemic cardiomyopathy.We studied a total of 89 minipigs; 63 completed the specified protocols. After NOGA-guided transendocardial injection, we quantified engraftment of escalating doses of allogeneic cardiospheres or cardiosphere-derived cells in minipigs (n = 22) post-MI. Next, a dose-ranging, blinded, randomized, placebo-controlled ("dose optimization") study of transendocardial injection of the better-engrafting product was performed in infarcted minipigs (n = 16). Finally, the superior product and dose (150 million cardiospheres) were tested in a blinded, randomized, placebo-controlled ("pivotal") study (n = 22). Contrast-enhanced cardiac MRI revealed that all cardiosphere doses preserved systolic function and attenuated remodeling. The maximum feasible dose (150 million cells) was most effective in reducing scar size, increasing viable myocardium and improving ejection fraction. In the pivotal study, eight weeks post-injection, histopathology demonstrated no excess inflammation, and no myocyte hypertrophy, in treated minipigs versus controls. No alloreactive donor-specific antibodies developed over time. MRI showed reduced scar size, increased viable mass, and attenuation of cardiac dilatation with no effect on ejection fraction in the treated group compared to placebo.Dose-optimized injection of allogeneic cardiospheres is safe, decreases scar size, increases viable myocardium, and attenuates cardiac dilatation in porcine chronic ischemic cardiomyopathy. The decreases in scar size, mirrored by increases in viable myocardium, are consistent with therapeutic regeneration.}, number={12}, journal={PLOS ONE}, author={Yee, Kristine and Malliaras, Konstantinos and Kanazawa, Hideaki and Tseliou, Eleni and Cheng, Ke and Luthringer, Daniel J. and Ho, Chak-Sum and Takayama, Kentaro and Minamino, Naoto and Dawkins, James F. and et al.}, year={2014}, month={Dec} }
 @article{cheng_ibrahim_hensley_sun_liu_smith_marban_2014, title={CD90/Thy-1-negative cardiosphere-derived cells exhibit augmented regenerative potency in humans and mice with myocardial infarction}, volume={3}, number={5}, journal={Journal of the American Heart Association}, author={Cheng, K and Ibrahim, A and Hensley, MT and Sun, B and Liu, W and Smith, RR and Marban, E}, year={2014}, pages={001260} }
 @article{xie_ibrahim_cheng_malliaras_shen_sun_cho_human_2014, title={Cardiosphere-derived Cells Stimulate Cardiomyocyte Proliferation via β1 Integrin Signaling}, volume={32}, journal={Stem Cells}, author={Xie, Y. and Ibrahim, A. and Cheng, K. and Malliaras, K. and Shen, D. and Sun, B. and Cho, H.C. and Human, Marbán E.}, year={2014}, pages={2397–2406} }
 @article{cingolani_ionta_cheng_giacomello_cho_marbán_2014, title={Engineered Electrical Conduction Tract Restores Conduction in Complete Heart Block}, volume={64}, ISSN={0735-1097}, url={http://dx.doi.org/10.1016/j.jacc.2014.09.056}, DOI={10.1016/j.jacc.2014.09.056}, abstractNote={Cardiac electrical conduction delays and blocks cause rhythm disturbances such as complete heart block, which can be fatal. Standard of care relies on electronic devices to artificially restore synchrony. We sought to create a new modality for treating these disorders by engineering electrical conduction tracts designed to propagate electrical impulses. This study sought to create a new approach for treating cardiac conduction disorders by using engineered electrical conduction tracts (EECTs). Paramagnetic beads were conjugated with an antibody to gamma-sarcoglycan, a cardiomyocyte cell surface antigen, and mixed with freshly isolated neonatal rat ventricular cardiomyocytes. A magnetic field was used to pattern a linear EECT. In an in vitro model of conduction block, the EECT was patterned so that it connected 2 independently beating neonatal rat ventricular cardiomyocyte monolayers; it achieved coordinated electrical activity, with action potentials propagating from 1 region to the other via EECT. Spiking the EECT with heart-derived stromal cells yielded stable structures with highly reproducible conduction velocities. Transplantation of EECTs in vivo restored atrioventricular conduction in a rat model of complete heart block. An EECT can re-establish electrical conduction in the heart. This novel approach could, in principle, be used not only to treat cardiac arrhythmias but also to repair other organs.}, number={24}, journal={Journal of the American College of Cardiology}, publisher={Elsevier BV}, author={Cingolani, Eugenio and Ionta, Vittoria and Cheng, Ke and Giacomello, Alessandro and Cho, Hee Cheol and Marbán, Eduardo}, year={2014}, month={Dec}, pages={2575–2585} }
 @article{ibrahim_cheng_marbán_2014, title={Exosomes as Critical Agents of Cardiac Regeneration Triggered by Cell Therapy}, volume={2}, ISSN={2213-6711}, url={http://dx.doi.org/10.1016/j.stemcr.2014.04.006}, DOI={10.1016/j.stemcr.2014.04.006}, abstractNote={The CADUCEUS trial of cardiosphere-derived cells (CDCs) has shown that it may be possible to regenerate injured heart muscle previously thought to be permanently scarred. The mechanisms of benefit are known to be indirect, but the mediators have yet to be identified. Here we pinpoint exosomes secreted by human CDCs as critical agents of regeneration and cardioprotection. CDC exosomes inhibit apoptosis and promote proliferation of cardiomyocytes, while enhancing angiogenesis. Injection of exosomes into injured mouse hearts recapitulates the regenerative and functional effects produced by CDC transplantation, whereas inhibition of exosome production by CDCs blocks those benefits. CDC exosomes contain a distinctive complement of microRNAs, with particular enrichment of miR-146a. Selective administration of a miR-146a mimic reproduces some (but not all) of the benefits of CDC exosomes. The findings identify exosomes as key mediators of CDC-induced regeneration, while highlighting the potential utility of exosomes as cell-free therapeutic candidates.}, number={5}, journal={Stem Cell Reports}, publisher={Elsevier BV}, author={Ibrahim, Ahmed Gamal-Eldin and Cheng, Ke and Marbán, Eduardo}, year={2014}, month={May}, pages={606–619} }
 @article{cheng_malliaras_smith_shen_sun_blusztajn_xie_ibrahim_aminzadeh_liu_et al._2014, title={Human Cardiosphere-Derived Cells From Advanced Heart Failure Patients Exhibit Augmented Functional Potency in Myocardial Repair}, volume={2}, ISSN={2213-1779}, url={http://dx.doi.org/10.1016/j.jchf.2013.08.008}, DOI={10.1016/j.jchf.2013.08.008}, abstractNote={This study sought to compare the regenerative potency of cells derived from healthy and diseased human hearts.Results from pre-clinical studies and the CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial support the notion that cardiosphere-derived cells (CDCs) from normal and recently infarcted hearts are capable of regenerating healthy heart tissue after myocardial infarction (MI). It is unknown whether CDCs derived from advanced heart failure (HF) patients retain the same regenerative potency.In a mouse model of acute MI, we compared the regenerative potential and functional benefits of CDCs derived from 3 groups: 1) non-failing (NF) donor: healthy donor hearts post-transplantation; 2) MI: patients who had an MI 9 to 35 days before biopsy; and 3) HF: advanced cardiomyopathy tissue explanted at cardiac transplantation.Cell growth and phenotype were identical in all 3 groups. Injection of HF CDCs led to the greatest therapeutic benefit in mice, with the highest left ventricular ejection fraction, thickest infarct wall, most viable tissue, and least scar 3 weeks after treatment. In vitro assays revealed that HF CDCs secreted higher levels of stromal cell-derived factor (SDF)-1, which may contribute to the cells' augmented resistance to oxidative stress, enhanced angiogenesis, and improved myocyte survival. Histological analysis indicated that HF CDCs engrafted better, recruited more endogenous stem cells, and induced greater angiogenesis and cardiomyocyte cell-cycle re-entry. CDC-secreted SDF-1 levels correlated with decreases in scar mass over time in CADUCEUS patients treated with autologous CDCs.CDCs from advanced HF patients exhibit augmented potency in ameliorating ventricular dysfunction post-MI, possibly through SDF-1–mediated mechanisms.}, number={1}, journal={JACC: Heart Failure}, publisher={Elsevier BV}, author={Cheng, Ke and Malliaras, Konstantinos and Smith, Rachel Ruckdeschel and Shen, Deliang and Sun, Baiming and Blusztajn, Agnieszka and Xie, Yucai and Ibrahim, Ahmed and Aminzadeh, Mohammad Amin and Liu, Weixin and et al.}, year={2014}, month={Feb}, pages={49–61} }
 @article{xie_ibrahim_cheng_wu_liang_malliaras_sun_liu_shen_cheol cho_et al._2014, title={Importance of Cell-Cell Contact in the Therapeutic Benefits of Cardiosphere-Derived Cells}, volume={32}, ISSN={1066-5099}, url={http://dx.doi.org/10.1002/STEM.1736}, DOI={10.1002/STEM.1736}, abstractNote={Abstract Cardiosphere-derived cells (CDCs) effect therapeutic regeneration after myocardial infarction (MI) both in animal models and in humans. Here, we test the hypothesis that cell-cell contact plays a role in mediating the observed therapeutic benefits of CDCs, above and beyond conventional paracrine effects. Human CDCs or vehicle were injected into immunodeficient (SCID) mouse hearts during acute MI. CDC transplantation augmented the proportion of cycling (Ki67+) cardiomyocytes and improved ventricular function. CDC-conditioned media only modestly augmented the percentage of Ki67+ cardiomyocytes (>control but <CDCs), but did not improve pump function. When neonatal rat ventricular myocytes (NRVMs) were cocultured with human CDCs in vitro, the percentage of cycling NRVMs (Ki67+ or BrdU+ nuclei) increased relative to solitary NRVM culture. To further dissect the relative contributions of soluble factors versus contact-dependent mechanisms, we compared CDCs grown with NRVMs in a transwell contact-free system versus admixed coculture. The percentage of cycling NRVMs was higher in admixed coculture than in the contact-free system. Pretreatment with inhibitors of MEK and PI3K, or with β1 integrin neutralizing antibody, blocked the ability of CDCs to promote myocyte cycling. While conditioned media are not inert, direct apposition of CDCs to cardiomyocytes produces greater enhancement of cardiomyocyte proliferation in vitro and in vivo, and improves function post-MI. Intact cardiomyocyte β1 integrin signaling is necessary for the contact-dependent cardioproliferative effects of CDCs. Stem Cells 2014;32:2397–2406}, number={9}, journal={STEM CELLS}, publisher={Wiley}, author={Xie, Yucai and Ibrahim, Ahmed and Cheng, Ke and Wu, Zhijun and Liang, Wenbin and Malliaras, Konstantinos and Sun, Baiming and Liu, Weixin and Shen, Deliang and Cheol Cho, Hee and et al.}, year={2014}, month={Aug}, pages={2397–2406} }
 @article{malliaras_makkar_smith_cheng_wu_bonow_marbán_mendizabal_cingolani_johnston_et al._2014, title={Intracoronary Cardiosphere-Derived Cells After Myocardial Infarction}, volume={63}, ISSN={0735-1097}, url={http://dx.doi.org/10.1016/j.jacc.2013.08.724}, DOI={10.1016/j.jacc.2013.08.724}, abstractNote={This study sought to report full 1-year results, detailed magnetic resonance imaging analysis, and determinants of efficacy in the prospective, randomized, controlled CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial. Cardiosphere-derived cells (CDCs) exerted regenerative effects at 6 months in the CADUCEUS trial. Complete results at the final 1-year endpoint are unknown. Autologous CDCs (12.5 to 25 × 106) grown from endomyocardial biopsy specimens were infused via the intracoronary route in 17 patients with left ventricular dysfunction 1.5 to 3 months after myocardial infarction (MI) (plus 1 infused off-protocol 14 months post-MI). Eight patients were followed as routine-care control patients. In 13.4 months of follow-up, safety endpoints were equivalent between groups. At 1 year, magnetic resonance imaging revealed that CDC-treated patients had smaller scar size compared with control patients. Scar mass decreased and viable mass increased in CDC-treated patients but not in control patients. The single patient infused 14 months post-MI responded similarly. CDC therapy led to improved regional function of infarcted segments compared with control patients. Scar shrinkage correlated with an increase in viability and with improvement in regional function. Scar reduction correlated with baseline scar size but not with a history of temporally remote MI or time from MI to infusion. The changes in left ventricular ejection fraction in CDC-treated subjects were consistent with the natural relationship between scar size and ejection fraction post-MI. Intracoronary administration of autologous CDCs did not raise significant safety concerns. Preliminary indications of bioactivity include decreased scar size, increased viable myocardium, and improved regional function of infarcted myocardium at 1 year post-treatment. These results, which are consistent with therapeutic regeneration, merit further investigation in future trials. (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction [CADUCEUS]; NCT00893360)}, number={2}, journal={Journal of the American College of Cardiology}, publisher={Elsevier BV}, author={Malliaras, Konstantinos and Makkar, Raj R. and Smith, Rachel R. and Cheng, Ke and Wu, Edwin and Bonow, Robert O. and Marbán, Linda and Mendizabal, Adam and Cingolani, Eugenio and Johnston, Peter V. and et al.}, year={2014}, month={Jan}, pages={110–122} }
 @article{cheng_shen_hensley_middleton_sun_liu_de couto_marbán_2014, title={Magnetic antibody-linked nanomatchmakers for therapeutic cell targeting}, volume={5}, ISSN={2041-1723}, url={http://dx.doi.org/10.1038/ncomms5880}, DOI={10.1038/ncomms5880}, abstractNote={Stem cell transplantation is a promising strategy for therapeutic cardiac regeneration, but current therapies are limited by inefficient interaction between potentially beneficial cells (either exogenously transplanted or endogenously recruited) and the injured tissue. Here we apply targeted nanomedicine to achieve in vivo cell-mediated tissue repair, imaging and localized enrichment without cellular transplantation. Iron nanoparticles are conjugated with two types of antibodies (one against antigens on therapeutic cells and the other directed at injured cells) to produce magnetic bifunctional cell engager (MagBICE). The antibodies link the therapeutic cells to the injured cells, whereas the iron core of MagBICE enables physical enrichment and imaging. We treat acute myocardial infarction by targeting exogenous bone marrow-derived stem cells (expressing CD45) or endogenous CD34-positive cells to injured cardiomyocytes (expressing myosin light chain. Targeting can be further enhanced by magnetic attraction, leading to augmented functional benefits. MagBICE represents a generalizable platform technology for regenerative medicine. Cell therapy requires sufficient amounts of therapeutic cells to be delivered to the injured tissue. Here the authors use magnetic iron nanoparticles conjugated with antibodies that bind therapeutic cells and cardiomyocytes to treat myocardial ischemia/reperfusion injury in rats and show that targeting to the heart is enhanced upon local application of a magnetic field.}, number={1}, journal={Nature Communications}, publisher={Springer Science and Business Media LLC}, author={Cheng, Ke and Shen, Deliang and Hensley, M. Taylor and Middleton, Ryan and Sun, Baiming and Liu, Weixin and De Couto, Geoffrey and Marbán, Eduardo}, year={2014}, month={Sep} }
 @article{vandergriff_hensley_henry_shen_anthony_zhang_cheng_2014, title={Magnetic targeting of cardiosphere-derived stem cells with ferumoxytol nanoparticles for treating rats with myocardial infarction}, volume={35}, ISSN={["1878-5905"]}, DOI={10.1016/j.biomaterials.2014.06.031}, abstractNote={Stem cell transplantation is a promising therapeutic strategy for acute or chronic ischemic cardiomyopathy. A major limitation to efficacy in cell transplantation is the low efficiency of retention and engraftment, due at least in part to significant early “wash-out” of cells from coronary blood flow and heart contraction . We sought to enhance cell retention and engraftment by magnetic targeting. Human cardiosphere-derived stem cells (hCDCs) were labeled with FDA-approved ferumoxytol nanoparticles Feraheme ® (F) in the presence of heparin (H) and protamine (P). FHP labeling is nontoxic to hCDCs. FHP-labeled rat CDCs (FHP-rCDCs) were intracoronarily infused into syngeneic rats, with and without magnetic targeting. Magnetic resonance imaging, fluorescence imaging, and quantitative PCR revealed magnetic targeting increased cardiac retention of transplanted FHP-rCDCs. Neither infusion of FHP-rCDCs nor magnetic targeting exacerbated cardiac inflammation or caused iron overload . The augmentation of acute cell retention translated into more attenuated left ventricular remodeling and greater therapeutic benefit (ejection fraction) 3 weeks after treatment. Histology revealed enhanced cell engraftment and angiogenesis in hearts from the magnetic targeting group. FHP labeling is safe to cardiac stem cells and facilitates magnetically-targeted stem cell delivery into the heart which leads to augmented cell engraftment and therapeutic benefit.}, number={30}, journal={BIOMATERIALS}, author={Vandergriff, Adam C. and Hensley, Taylor M. and Henry, Eric T. and Shen, Deliang and Anthony, Shirena and Zhang, Jinying and Cheng, Ke}, year={2014}, month={Oct}, pages={8528–8539} }
 @article{cheng_ibrahim_hensley_shen_sun_middleton_liu_smith_marban_2014, title={Relative Roles of CD90 and c-Kit to the Regenerative Efficacy of Cardiosphere-Derived Cells in Humans and in a Mouse Model of Myocardial Infarction}, volume={3}, ISSN={["2047-9980"]}, DOI={10.1161/jaha.114.001260}, abstractNote={Background The regenerative potential of cardiosphere‐derived cells ( CDC s) for ischemic heart disease has been demonstrated in mice, rats, pigs, and a recently completed clinical trial ( CADUCEUS ). CDC s are CD 105 + stromal cells of intrinsic cardiac origin, but the antigenic characteristics of the active fraction remain to be defined. CDC s contain a small minority of c‐kit + cells, which have been argued to be cardiac progenitors, and a variable fraction of CD 90 + cells whose bioactivity is unclear. Methods We performed a retrospective analysis of data from the CADUCEUS trial and a prospective mouse study to elucidate the roles of c‐kit + and CD 90 + cells in human CDC s. Here, we show, surprisingly, that c‐kit expression has no relationship to CDC s' therapeutic efficacy in humans, and depletion of c‐kit + cells does not undermine the structural and functional benefits of CDC s in a mouse model of myocardial infarction (MI). In contrast, CD 90 expression negatively correlates with the therapeutic benefit of CDC s in humans (ie, higher CD 90 expression associated with lower efficacy). Depletion of CD 90 + cells augments the functional potency of CDC s in murine MI. CD 90 − CDC s secrete lower levels of inflammatory cytokines and can differentiate into cardiomyocytes in vitro and in vivo. Conclusion The majority population of CDC s ( CD 105 + / CD 90 − /c‐kit − ) constitutes the active fraction, both in terms of therapeutic efficacy and in the ability to undergo cardiomyogenic differentiation. The c‐kit + fraction is neither necessary for, nor contributory to, the regenerative efficacy of CDC s.}, number={5}, journal={JOURNAL OF THE AMERICAN HEART ASSOCIATION}, author={Cheng, Ke and Ibrahim, Ahmed and Hensley, M. Taylor and Shen, Deliang and Sun, Baiming and Middleton, Ryan and Liu, Weixin and Smith, Rachel R. and Marban, Eduardo}, year={2014}, month={Oct} }
 @article{aminzadeh_tseliou_sun_cheng_malliaras_makkar_marban_2014, title={Therapeutic efficacy of cardiosphere-derived cells in a transgenic mouse model of non-ischaemic dilated cardiomyopathy}, volume={36}, ISSN={0195-668X 1522-9645}, url={http://dx.doi.org/10.1093/eurheartj/ehu196}, DOI={10.1093/eurheartj/ehu196}, abstractNote={Cardiosphere-derived cells (CDCs) produce regenerative effects in the post-infarct setting. However, it is unclear whether CDCs are beneficial in non-ischaemic dilated cardiomyopathy (DCM). We tested the effects of CDC transplantation in mice with cardiac-specific Gαq overexpression, which predictably develop progressive cardiac dilation and failure, with accelerated mortality.Wild-type mouse CDCs (10(5) cells) or vehicle only were injected intramyocardially in 6-, 8-, and 11-week-old Gαq mice. Cardiac function deteriorated in vehicle-treated mice over 3 months of follow-up, accompanied by oxidative stress, inflammation and adverse ventricular remodelling. In contrast, CDCs preserved cardiac function and volumes, improved survival, and promoted cardiomyogenesis while blunting Gαq-induced oxidative stress and inflammation in the heart. The mechanism of benefit is indirect, as long-term engraftment of transplanted cells is vanishingly low.Cardiosphere-derived cells reverse fundamental abnormalities in cell signalling, prevent adverse remodelling, and improve survival in a mouse model of DCM. The ability to impact favourably on disease progression in non-ischaemic heart failure heralds new potential therapeutic applications of CDCs.}, number={12}, journal={European Heart Journal}, publisher={Oxford University Press (OUP)}, author={Aminzadeh, M. A. and Tseliou, E. and Sun, B. and Cheng, K. and Malliaras, K. and Makkar, R. R. and Marban, E.}, year={2014}, month={May}, pages={751–762} }
 @article{malliaras_zhang_seinfeld_galang_tseliou_cheng_sun_aminzadeh_marbán_2013, title={Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart}, volume={5}, ISSN={1757-4676}, url={http://dx.doi.org/10.1002/emmm.201201737}, DOI={10.1002/emmm.201201737}, abstractNote={Cardiosphere-derived cells (CDCs) have been shown to regenerate infarcted myocardium in patients after myocardial infarction (MI). However, whether the cells of the newly formed myocardium originate from the proliferation of adult cardiomyocytes or from the differentiation of endogenous stem cells remains unknown. Using genetic fate mapping to mark resident myocytes in combination with long-term BrdU pulsing, we investigated the origins of postnatal cardiomyogenesis in the normal, infarcted and cell-treated adult mammalian heart. In the normal mouse heart, cardiomyocyte turnover occurs predominantly through proliferation of resident cardiomyocytes at a rate of ∼1.3-4%/year. After MI, new cardiomyocytes arise from both progenitors as well as pre-existing cardiomyocytes. Transplantation of CDCs upregulates host cardiomyocyte cycling and recruitment of endogenous progenitors, while boosting heart function and increasing viable myocardium. The observed phenomena cannot be explained by cardiomyocyte polyploidization, bi/multinucleation, cell fusion or DNA repair. Thus, CDCs induce myocardial regeneration by differentially upregulating two mechanisms of endogenous cell proliferation.}, number={2}, journal={EMBO Molecular Medicine}, publisher={EMBO}, author={Malliaras, Konstantinos and Zhang, Yiqiang and Seinfeld, Jeffrey and Galang, Giselle and Tseliou, Eleni and Cheng, Ke and Sun, Baiming and Aminzadeh, Mohammad and Marbán, Eduardo}, year={2013}, month={Jan}, pages={191–209} }
 @article{malliaras_cheng_smith_wu_bonow_mendizabal_gerstenblith_johnston_schuleri_lardo_et al._2013, title={INTRACORONARY CARDIOSPHERE-DERIVED CELLS AFTER MYOCARDIAL INFARCTION: MAGNETIC RESONANCE IMAGING ANALYSIS OF REGENERATION AND DETERMINANTS OF EFFICACY IN THE FINAL 1-YEAR RESULTS OF THE CADUCEUS TRIAL}, volume={61}, ISSN={0735-1097}, url={http://dx.doi.org/10.1016/S0735-1097(13)60105-9}, DOI={10.1016/S0735-1097(13)60105-9}, abstractNote={Cardiosphere-derived cells (CDCs) exert regenerative effects in post-MI patients with LV dysfunction in the CADUCEUS trial. Here we report full 1-year results and correlates of efficacy.

Autologous CDCs (12.5-25×106) grown from endomyocardial biopsies were infused into the infarct-related artery}, number={10}, journal={Journal of the American College of Cardiology}, publisher={Elsevier BV}, author={Malliaras, Konstantinos and Cheng, Ke and Smith, Rachel R. and Wu, Edwin and Bonow, Robert and Mendizabal, Adam and Gerstenblith, Gary and Johnston, Peter V. and Schuleri, Karl and Lardo, Albert C. and et al.}, year={2013}, month={Mar}, pages={E104} }
 @article{malliaras_smith_kanazawa_yee_seinfeld_tseliou_dawkins_kreke_cheng_luthringer_et al._2013, title={Validation of Contrast-Enhanced Magnetic Resonance Imaging to Monitor Regenerative Efficacy After Cell Therapy in a Porcine Model of Convalescent Myocardial Infarction}, volume={128}, ISSN={0009-7322 1524-4539}, url={http://dx.doi.org/10.1161/circulationaha.113.002863}, DOI={10.1161/circulationaha.113.002863}, abstractNote={Background— Magnetic resonance imaging (MRI) in the CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial revealed that cardiosphere-derived cells (CDCs) decrease scar size and increase viable myocardium after myocardial infarction (MI), but MRI has not been validated as an index of regeneration after cell therapy. We tested the validity of contrast-enhanced MRI in quantifying scarred and viable myocardium after cell therapy in a porcine model of convalescent MI. Methods and Results— Yucatan minipigs underwent induction of MI and 2–3 weeks later were randomized to receive intracoronary infusion of 12.5×10 6 mismatched allogeneic CDCs or vehicle. Allogeneic CDCs induced mild local mononuclear infiltration but no systemic immunogenicity. MRI revealed that allogeneic CDCs attenuated remodeling, improved global and regional function, decreased scar size, and increased viable myocardium compared with placebo 2 months post-treatment. Extensive histological analysis validated quantitatively the MRI measurements of scar size, scar mass, and viable mass. CDCs neither altered gadolinium contrast myocardial kinetics nor induced changes in vascular density or architecture in viable and scarred myocardium. Histology demonstrated that CDCs lead to cardiomyocyte hyperplasia in the border zone, consistent with the observed stimulation of endogenous regenerative mechanisms (cardiomyocyte cycling, upregulation of endogenous progenitors, angiogenesis). Conclusions— Contrast-enhanced MRI accurately measures scarred and viable myocardium after cell therapy in a porcine model of convalescent MI. MRI represents a useful tool for assessing dynamic changes in the infarct and monitoring regenerative efficacy.}, number={25}, journal={Circulation}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Malliaras, Konstantinos and Smith, Rachel R. and Kanazawa, Hideaki and Yee, Kristine and Seinfeld, Jeffrey and Tseliou, Eleni and Dawkins, James F. and Kreke, Michelle and Cheng, Ke and Luthringer, Daniel and et al.}, year={2013}, month={Dec}, pages={2764–2775} }
 @article{cheng_shen_xie_cingolani_malliaras_marbán_2012, title={Brief Report: Mechanism of Extravasation of Infused Stem Cells}, volume={30}, ISSN={1066-5099}, url={http://dx.doi.org/10.1002/stem.1184}, DOI={10.1002/stem.1184}, abstractNote={In order for bloodborne stem cells to be effective in tissue regeneration, cells must cross vessel walls and enter the parenchyma. Although such transmigration does occur, the mechanism remains elusive. Leukocytes invade tissue by diapedesis; stem cells are commonly assumed to do likewise, but evidence is lacking. Cardiac-derived regenerative cells and multicellular cardiospheres (CSPs) were infused into the coronary vessels of rat hearts. Serial histology revealed a novel mechanism of cell transmigration, “active vascular expulsion,” which underlies the extravasation of infused cells and cell aggregates. In this mechanism, the vascular barrier undergoes extensive remodeling, while the cells themselves are relatively passive. The mechanism was confirmed in vivo by serial intravital microscopy of CSP extravasation in a dorsal skin flap model. Integrins and matrix metalloproteinases play critical roles in active vascular expulsion. In vitro models revealed that active vascular expulsion is generalizable to other stem cell types and to breast cancer cells. Recognition of active vascular expulsion as a mechanism for transvascular cell migration opens new opportunities to enhance the efficacy of vascularly delivered cell therapy.}, number={12}, journal={STEM CELLS}, publisher={Wiley}, author={Cheng, Ke and Shen, Deliang and Xie, Yucai and Cingolani, Eugenio and Malliaras, Konstantinos and Marbán, Eduardo}, year={2012}, month={Nov}, pages={2835–2842} }
 @article{li_cheng_malliaras_smith_zhang_sun_matsushita_blusztajn_terrovitis_kusuoka_et al._2012, title={Direct Comparison of Different Stem Cell Types and Subpopulations Reveals Superior Paracrine Potency and Myocardial Repair Efficacy With Cardiosphere-Derived Cells}, volume={59}, ISSN={0735-1097}, url={http://dx.doi.org/10.1016/j.jacc.2011.11.029}, DOI={10.1016/j.jacc.2011.11.029}, abstractNote={The goal of this study was to conduct a direct head-to-head comparison of different stem cell types in vitro for various assays of potency and in vivo for functional myocardial repair in the same mouse model of myocardial infarction. Adult stem cells of diverse origins (e.g., bone marrow, fat, heart) and antigenic identity have been studied for repair of the damaged heart, but the relative utility of the various cell types remains unclear. Human cardiosphere-derived cells (CDCs), bone marrow–derived mesenchymal stem cells, adipose tissue–derived mesenchymal stem cells, and bone marrow mononuclear cells were compared. CDCs revealed a distinctive phenotype with uniform expression of CD105, partial expression of c-kit and CD90, and negligible expression of hematopoietic markers. In vitro, CDCs showed the greatest myogenic differentiation potency, highest angiogenic potential, and relatively high production of various angiogenic and antiapoptotic-secreted factors. In vivo, injection of CDCs into the infarcted mouse hearts resulted in superior improvement of cardiac function, the highest cell engraftment and myogenic differentiation rates, and the least-abnormal heart morphology 3 weeks after treatment. CDC-treated hearts also exhibited the lowest number of apoptotic cells. The c-kit+ subpopulation purified from CDCs produced lower levels of paracrine factors and inferior functional benefit when compared with unsorted CDCs. To validate the comparison of cells from various human donors, selected results were confirmed in cells of different types derived from individual rats. CDCs exhibited a balanced profile of paracrine factor production and, among various comparator cell types/subpopulations, provided the greatest functional benefit in experimental myocardial infarction.}, number={10}, journal={Journal of the American College of Cardiology}, publisher={Elsevier BV}, author={Li, Tao-Sheng and Cheng, Ke and Malliaras, Konstantinos and Smith, Rachel Ruckdeschel and Zhang, Yiqiang and Sun, Baiming and Matsushita, Noriko and Blusztajn, Agnieszka and Terrovitis, John and Kusuoka, Hideo and et al.}, year={2012}, month={Mar}, pages={942–953} }
 @article{shen_cheng_marbán_2012, title={Dose-dependent functional benefit of human cardiosphere transplantation in mice with acute myocardial infarction}, volume={16}, ISSN={1582-1838}, url={http://dx.doi.org/10.1111/j.1582-4934.2011.01512.x}, DOI={10.1111/j.1582-4934.2011.01512.x}, abstractNote={Despite mounting pre-clinical and clinical evidence of the beneficial effects of cell-based therapy, optimal cell dosing and delivery approaches have not been identified. Cardiospheres are self-assembling three-dimensional (3D) microtissues formed by cardiac stem cells and supporting cell types. The ability of cardiospheres to augment cardiac function has been demonstrated in animal models of ischemic cardiomyopathy. In this study, we studied the dose dependence of the benefits of human cardiospheres, delivered via intramyocardial injection, upon cardiac function and ventricular remodelling in SCID mice with acute myocardial infarction. Four doses of cardiospheres were used: 1 × 10(4), 5 × 10(4), 1 × 10(5) and 5 × 10(5) (expressed as number of plated cardiosphere-forming cells). Acute (24 hr) cell retention rates in all groups were similar. Functional assessment and quantitative heart morphometry indicated benefit from higher cell doses (≥5 × 10(4)) in terms of ejection fraction, infarct size and capillary density. Histological analysis indicated that the dose-dependent benefit was primarily because of indirect effects of transplanted cells. The results provide scalable data on cardiosphere dosing for intramyocardial injection.}, number={9}, journal={Journal of Cellular and Molecular Medicine}, publisher={Wiley}, author={Shen, Deliang and Cheng, Ke and Marbán, Eduardo}, year={2012}, month={Aug}, pages={2112–2116} }
 @article{cheng_blusztajn_shen_li_sun_galang_zarembinski_prestwich_marbán_smith_et al._2012, title={Functional performance of human cardiosphere-derived cells delivered in an in situ polymerizable hyaluronan-gelatin hydrogel}, volume={33}, ISSN={0142-9612}, url={http://dx.doi.org/10.1016/j.biomaterials.2012.04.006}, DOI={10.1016/j.biomaterials.2012.04.006}, abstractNote={The vast majority of cells delivered into the heart by conventional means are lost within the first 24 h. Methods are needed to enhance cell retention, so as to minimize loss of precious material and maximize effectiveness of the therapy. We tested a cell-hydrogel delivery strategy. Cardiosphere-derived cells (CDCs) were grown from adult human cardiac biopsy specimens. In situ polymerizable hydrogels made of hyaluronan and porcine gelatin (Hystem(®)-C™) were formulated as a liquid at room temperature so as to gel within 20 min at 37 °C. CDC viability and migration were not compromised in Hystem-C™. Myocardial infarction was created in SCID mice and CDCs were injected intramyocardially in the infarct border zone. Real-time PCR revealed engraftment of CDCs delivered in Hystem-C™ was increased by nearly an order of magnitude. LVEF (left ventricular ejection fraction) deteriorated in the control (PBS only) group over the 3-week time course. Hystem-C™ alone or CDCs alone preserved LVEF relative to baseline, while CDCs delivered in Hystem-C™ resulted in a sizable boost in LVEF. Heart morphometry revealed the greatest attenuation of LV remodeling in the CDC + Hystem-C™ group. Histological analysis suggested cardiovascular differentiation of the CDCs in Hystem-C™. However, the majority of functional benefit is likely from paracrine mechanisms such as tissue preservation and neovascularization. A CDC/hydrogel formulation suitable for catheter-based intramyocardial injection exhibits superior engraftment and functional benefits relative to naked CDCs.}, number={21}, journal={Biomaterials}, publisher={Elsevier BV}, author={Cheng, Ke and Blusztajn, Agnieszka and Shen, Deliang and Li, Tao-Sheng and Sun, Baiming and Galang, Giselle and Zarembinski, Thomas I. and Prestwich, Glenn D. and Marbán, Eduardo and Smith, Rachel R. and et al.}, year={2012}, month={Jul}, pages={5317–5324} }
 @article{makkar_smith_cheng_malliaras_thomson_berman_czer_marbán_mendizabal_johnston_et al._2012, title={Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial}, volume={379}, ISSN={0140-6736}, url={http://dx.doi.org/10.1016/s0140-6736(12)60195-0}, DOI={10.1016/s0140-6736(12)60195-0}, abstractNote={<h2>Summary</h2><h3>Background</h3> Cardiosphere-derived cells (CDCs) reduce scarring after myocardial infarction, increase viable myocardium, and boost cardiac function in preclinical models. We aimed to assess safety of such an approach in patients with left ventricular dysfunction after myocardial infarction. <h3>Methods</h3> In the prospective, randomised CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial, we enrolled patients 2–4 weeks after myocardial infarction (with left ventricular ejection fraction of 25–45%) at two medical centres in the USA. An independent data coordinating centre randomly allocated patients in a 2:1 ratio to receive CDCs or standard care. For patients assigned to receive CDCs, autologous cells grown from endomyocardial biopsy specimens were infused into the infarct-related artery 1·5–3 months after myocardial infarction. The primary endpoint was proportion of patients at 6 months who died due to ventricular tachycardia, ventricular fibrillation, or sudden unexpected death, or had myocardial infarction after cell infusion, new cardiac tumour formation on MRI, or a major adverse cardiac event (MACE; composite of death and hospital admission for heart failure or non-fatal recurrent myocardial infarction). We also assessed preliminary efficacy endpoints on MRI by 6 months. Data analysers were masked to group assignment. This study is registered with ClinicalTrials.gov, NCT00893360. <h3>Findings</h3> Between May 5, 2009, and Dec 16, 2010, we randomly allocated 31 eligible participants of whom 25 were included in a per-protocol analysis (17 to CDC group and eight to standard of care). Mean baseline left ventricular ejection fraction (LVEF) was 39% (SD 12) and scar occupied 24% (10) of left ventricular mass. Biopsy samples yielded prescribed cell doses within 36 days (SD 6). No complications were reported within 24 h of CDC infusion. By 6 months, no patients had died, developed cardiac tumours, or MACE in either group. Four patients (24%) in the CDC group had serious adverse events compared with one control (13%; p=1·00). Compared with controls at 6 months, MRI analysis of patients treated with CDCs showed reductions in scar mass (p=0·001), increases in viable heart mass (p=0·01) and regional contractility (p=0·02), and regional systolic wall thickening (p=0·015). However, changes in end-diastolic volume, end-systolic volume, and LVEF did not differ between groups by 6 months. <h3>Interpretation</h3> We show intracoronary infusion of autologous CDCs after myocardial infarction is safe, warranting the expansion of such therapy to phase 2 study. The unprecedented increases we noted in viable myocardium, which are consistent with therapeutic regeneration, merit further assessment of clinical outcomes. <h3>Funding</h3> US National Heart, Lung and Blood Institute and Cedars-Sinai Board of Governors Heart Stem Cell Center.}, number={9819}, journal={The Lancet}, publisher={Elsevier BV}, author={Makkar, Raj R and Smith, Rachel R and Cheng, Ke and Malliaras, Konstantinos and Thomson, Louise EJ and Berman, Daniel and Czer, Lawrence SC and Marbán, Linda and Mendizabal, Adam and Johnston, Peter V and et al.}, year={2012}, month={Mar}, pages={895–904} }
 @article{cheng_malliaras_shen_tseliou_ionta_smith_galang_sun_houde_marbán_2012, title={Intramyocardial Injection of Platelet Gel Promotes Endogenous Repair and Augments Cardiac Function in Rats With Myocardial Infarction}, volume={59}, ISSN={0735-1097}, url={http://dx.doi.org/10.1016/j.jacc.2011.10.858}, DOI={10.1016/j.jacc.2011.10.858}, abstractNote={This study sought to explore the therapeutic potential of platelet gel for the treatment of myocardial infarction. Cardiac dysfunction after acute myocardial infarction is a major cause of heart failure. Current therapy relies on prompt reperfusion and blockage of secondary maladaptive pathways by small molecules. Platelet gels are biomaterials rich in cytokines and growth factors, which can be manufactured in an autologous manner and are effective in various models of wound healing. However, the potential utility of platelet gel in cardiac regeneration has yet to be tested. Platelet gel was derived from syngeneic rats and its morphology, biocompatibility, secretion of beneficial factors, and in vivo degradation profile were characterized. After delivery into infarcted rat hearts, the gel was efficiently infiltrated by cardiomyocytes and endothelial cells. Gel-treated hearts exhibited enhanced tissue protection, greater recruitment of endogenous regeneration, higher capillary density, and less compensatory myocyte hypertrophy. The cardiac function of control-injected animals deteriorated over the 6-week time course, while that of platelet gel-injected animals did not. In addition, the gel did not exacerbate inflammation in the heart. Intramyocardial injection of autologous platelet gel ameliorated cardiac dysfunction after myocardial infarction. The striking functional benefits, the simplicity of manufacturing, and the potentially autologous nature of this biomaterial provide impetus for further translation.}, number={3}, journal={Journal of the American College of Cardiology}, publisher={Elsevier BV}, author={Cheng, Ke and Malliaras, Konstantinos and Shen, Deliang and Tseliou, Eleni and Ionta, Vittoria and Smith, Jeremy and Galang, Giselle and Sun, Baiming and Houde, Christiane and Marbán, Eduardo}, year={2012}, month={Jan}, pages={256–264} }
 @article{malliaras_li_luthringer_terrovitis_cheng_chakravarty_galang_zhang_schoenhoff_van eyk_et al._2012, title={Safety and Efficacy of Allogeneic Cell Therapy in Infarcted Rats Transplanted With Mismatched Cardiosphere-Derived Cells}, volume={125}, ISSN={0009-7322 1524-4539}, url={http://dx.doi.org/10.1161/circulationaha.111.042598}, DOI={10.1161/circulationaha.111.042598}, abstractNote={Cardiosphere-derived cells (CDCs) are an attractive cell type for tissue regeneration, and autologous CDCs are being tested clinically. However, autologous therapy necessitates patient-specific tissue harvesting and cell processing, with delays to therapy and possible variations in cell potency. The use of allogeneic CDCs, if safe and effective, would obviate such limitations. We compared syngeneic and allogeneic CDC transplantation in rats from immunologically-mismatched inbred strains.In vitro, CDCs expressed major histocompatibility complex class I but not class II antigens or B7 costimulatory molecules. In mixed-lymphocyte cocultures, allogeneic CDCs elicited negligible lymphocyte proliferation and inflammatory cytokine secretion. In vivo, syngeneic and allogeneic CDCs survived at similar levels in the infarcted rat heart 1 week after delivery, but few syngeneic (and even fewer allogeneic) CDCs remained at 3 weeks. Allogeneic CDCs induced a transient, mild, local immune reaction in the heart, without histologically evident rejection or systemic immunogenicity. Improvements in cardiac structure and function, sustained for 6 months, were comparable with syngeneic and allogeneic CDCs. Allogeneic CDCs stimulated endogenous regenerative mechanisms (cardiomyocyte cycling, recruitment of c-kit(+) cells, angiogenesis) and increased myocardial vascular endothelial growth factor, insulin-like growth factor-1, and hepatocyte growth factor equally with syngeneic CDCs.Allogeneic CDC transplantation without immunosuppression is safe, promotes cardiac regeneration, and improves heart function in a rat myocardial infarction model, mainly through stimulation of endogenous repair mechanisms. The indirect mechanism of action rationalizes the persistence of benefit despite the evanescence of transplanted cell survival. This work motivates the testing of allogeneic human CDCs as a potential off-the-shelf product for cellular cardiomyoplasty.}, number={1}, journal={Circulation}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Malliaras, Konstantinos and Li, Tao-Sheng and Luthringer, Daniel and Terrovitis, John and Cheng, Ke and Chakravarty, Tarun and Galang, Giselle and Zhang, Yiqiang and Schoenhoff, Florian and Van Eyk, Jennifer and et al.}, year={2012}, month={Jan}, pages={100–112} }
 @article{lai_cheng_kisaalita_2012, title={Three Dimensional Neuronal Cell Cultures More Accurately Model Voltage Gated Calcium Channel Functionality in Freshly Dissected Nerve Tissue}, volume={7}, ISSN={1932-6203}, url={http://dx.doi.org/10.1371/journal.pone.0045074}, DOI={10.1371/journal.pone.0045074}, abstractNote={It has been demonstrated that neuronal cells cultured on traditional flat surfaces may exhibit exaggerated voltage gated calcium channel (VGCC) functionality. To gain a better understanding of this phenomenon, primary neuronal cells harvested from mice superior cervical ganglion (SCG) were cultured on two dimensional (2D) flat surfaces and in three dimensional (3D) synthetic poly-L-lactic acid (PLLA) and polystyrene (PS) polymer scaffolds. These 2D- and 3D-cultured cells were compared to cells in freshly dissected SCG tissues, with respect to intracellular calcium increase in response to high K(+) depolarization. The calcium increases were identical for 3D-cultured and freshly dissected, but significantly higher for 2D-cultured cells. This finding established the physiological relevance of 3D-cultured cells. To shed light on the mechanism behind the exaggerated 2D-cultured cells' functionality, transcriptase expression and related membrane protein distributions (caveolin-1) were obtained. Our results support the view that exaggerated VGCC functionality from 2D cultured SCG cells is possibly due to differences in membrane architecture, characterized by uniquely organized caveolar lipid rafts. The practical implication of use of 3D-cultured cells in preclinical drug discovery studies is that such platforms would be more effective in eliminating false positive hits and as such improve the overall yield from screening campaigns.}, number={9}, journal={PLoS ONE}, publisher={Public Library of Science (PLoS)}, author={Lai, Yinzhi and Cheng, Ke and Kisaalita, William}, editor={Cymbalyuk, GennadyEditor}, year={2012}, month={Sep}, pages={e45074} }
 @article{cheng_shen_smith_galang_sun_zhang_marbán_2012, title={Transplantation of platelet gel spiked with cardiosphere-derived cells boosts structural and functional benefits relative to gel transplantation alone in rats with myocardial infarction}, volume={33}, ISSN={0142-9612}, url={http://dx.doi.org/10.1016/j.biomaterials.2011.12.040}, DOI={10.1016/j.biomaterials.2011.12.040}, abstractNote={The emerging field of stem cell therapy and biomaterials has begun to provide promising strategies for the treatment of ischemic cardiomyopathy. Platelet gel and cardiosphere-derived cells (CDCs) are known to be beneficial when transplanted separately post-myocardial infarction (MI). We hypothesize that pre-seeding platelet gel with CDCs can enhance therapeutic efficacy. Platelet gel and CDCs were derived from venous blood and heart biopsies of syngeneic rats, respectively. In vitro, the viability, growth, and morphology of CDCs cultured in platelet gel were characterized. When delivered into infarcted rat hearts, platelet gel pre-seeded with CDCs was more efficiently populated with endogenous cardiomyocytes and endothelial cells than platelet gel alone. Recruitment of endogenous c-kit positive cells was enhanced in the hearts treated with gel with CDC. At 3 weeks, the hearts treated with CDC-seeded platelet gel exhibited the greatest attenuation of adverse left ventricular (LV) remodeling and the highest cardiac function (i.e., LV ejection fraction) as compared to hearts transplanted with Gel only or vehicle controls. Histological analysis revealed that, though some transplanted CDCs differentiated into cardiomyocytes and endothelial cells in the recipients' hearts, most of the incremental benefit arose from CDC-mediated endogenous repair. Pre-seeding platelet gel with CDCs enhanced the functional benefit of biomaterial therapy for treating myocardial infarction.}, number={10}, journal={Biomaterials}, publisher={Elsevier BV}, author={Cheng, Ke and Shen, Deliang and Smith, Jeremy and Galang, Giselle and Sun, Baiming and Zhang, Jinying and Marbán, Eduardo}, year={2012}, month={Apr}, pages={2872–2879} }
 @article{lai_asthana_cheng_kisaalita_2011, title={Neural Cell 3D Microtissue Formation Is Marked by Cytokines' Up-Regulation}, volume={6}, ISSN={1932-6203}, url={http://dx.doi.org/10.1371/journal.pone.0026821}, DOI={10.1371/journal.pone.0026821}, abstractNote={Cells cultured in three dimensional (3D) scaffolds as opposed to traditional two-dimensional (2D) substrates have been considered more physiologically relevant based on their superior ability to emulate the in vivo environment. Combined with stem cell technology, 3D cell cultures can provide a promising alternative for use in cell-based assays or biosensors in non-clinical drug discovery studies. To advance 3D culture technology, a case has been made for identifying and validating three-dimensionality biomarkers. With this goal in mind, we conducted a transcriptomic expression comparison among neural progenitor cells cultured on 2D substrates, 3D porous polystyrene scaffolds, and as 3D neurospheres (in vivo surrogate). Up-regulation of cytokines as a group in 3D and neurospheres was observed. A group of 13 cytokines were commonly up-regulated in cells cultured in polystyrene scaffolds and neurospheres, suggesting potential for any or a combination from this list to serve as three-dimensionality biomarkers. These results are supportive of further cytokine identification and validation studies with cells from non-neural tissue.}, number={10}, journal={PLoS ONE}, publisher={Public Library of Science (PLoS)}, author={Lai, Yinzhi and Asthana, Amish and Cheng, Ke and Kisaalita, William S.}, editor={Wanunu, MeniEditor}, year={2011}, month={Oct}, pages={e26821} }
 @article{makkar_smith_cheng_malliaras_thomson_berman_czer_marbán_mendizabal_johnston_et al._2011, title={The CADUCEUS (CArdiosphere-Derived aUtologous Stem CElls to Reverse ventricUlar dySfunction) Trial}, volume={124}, journal={Circulation}, author={Makkar, R. and Smith, R.R. and Cheng, K. and Malliaras, K. and Thomson, L.E. and Berman, D.S. and Czer, L. and Marbán, L. and Mendizabal, A. and Johnston, P.V. and et al.}, year={2011}, pages={2365–2374} }
 @article{shen_wang_zhang_zhao_li_cheng_zhang_2011, title={The amelioration of cardiac dysfunction after myocardial infarction by the injection of keratin biomaterials derived from human hair}, volume={32}, ISSN={0142-9612}, url={http://dx.doi.org/10.1016/j.biomaterials.2011.08.057}, DOI={10.1016/j.biomaterials.2011.08.057}, abstractNote={Cardiac dysfunction following acute myocardial infarction is a major cause of advanced cardiomyopathy. Conventional pharmacological therapies rely on prompt reperfusion and prevention of repetitive maladaptive pathways. Keratin biomaterials can be manufactured in an autologous fashion and are effective in various models of tissue regeneration. However, its potential application in cardiac regeneration has not been tested. Keratin biomaterials were derived from human hair and its structure morphology, carryover of beneficial factors, biocompatibility with cardiomyocytes, and in vivo degradation profile were characterized. After delivery into infarcted rat hearts, the keratin scaffolds were efficiently infiltrated by cardiomyocytes and endothelial cells. Injection of keratin biomaterials promotes angiogenesis but does not exacerbate inflammation in the post-MI hearts. Compared to control-injected animals, keratin biomaterials-injected animals exhibited preservation of cardiac function and attenuation of adverse ventricular remodeling over the 8 week following time course. Tissue western blot analysis revealed up-regulation of beneficial factors (BMP4, NGF, TGF-beta) in the keratin-injected hearts. The salient functional benefits, the simplicity of manufacturing and the potentially autologous nature of this biomaterial provide impetus for further translation to the clinic.}, number={35}, journal={Biomaterials}, publisher={Elsevier BV}, author={Shen, Deliang and Wang, Xiaofang and Zhang, Li and Zhao, Xiaoyan and Li, Jingyi and Cheng, Ke and Zhang, Jinying}, year={2011}, month={Dec}, pages={9290–9299} }
 @article{li_cheng_lee_matsushita_davis_malliaras_zhang_matsushita_smith_marbán_2010, title={Cardiospheres Recapitulate a Niche-Like Microenvironment Rich in Stemness and Cell-Matrix Interactions, Rationalizing Their Enhanced Functional Potency for Myocardial Repair}, volume={28}, ISSN={1066-5099}, url={http://dx.doi.org/10.1002/stem.532}, DOI={10.1002/stem.532}, abstractNote={Abstract Cardiac stem cells (CSCs) are promising candidates for use in myocardial regenerative therapy. We test the hypothesis that growing cardiac-derived cells as three-dimensional cardiospheres may recapitulate a stem cell niche-like microenvironment, favoring cell survival and enhancing functional benefit after transplantation into the injured heart. CSCs and supporting cells from human endomyocardial biopsies were grown as cardiospheres and compared with cells cultured under traditional monolayer condition or dissociated from cardiospheres. Cardiospheres self-assembled into stem cell niche-like structures in vitro in suspension culture, while exhibiting greater proportions of c-kit+ cells and upregulated expression of SOX2 and Nanog. Pathway-focused polymerase chain reaction (PCR) array, quantitative real-time PCR, and immunostaining revealed enhanced expression of stem cell-relevant factors and adhesion/extracellular-matrix molecules (ECM) in cardiospheres including IGF-1, histone deacetylase 2 (HDAC2), Tert, integrin-α2, laminin-β1, and matrix metalloproteinases (MMPs). Implantation of cardiospheres in severe combined immunodeficiency (SCID) mouse hearts with acute infarction disproportionately improved cell engraftment and myocardial function, relative to monolayer-cultured cells. Dissociation of cardiospheres into single cells decreased the expression of ECM and adhesion molecules and undermined resistance to oxidative stress, negating the improved cell engraftment and functional benefit in vivo. Growth of cardiac-derived cells as cardiospheres mimics stem cell niche properties with enhanced “stemness” and expression of ECM and adhesion molecules. These changes underlie an increase in cell survival and more potent augmentation of global function following implantation into the infarcted heart.}, number={11}, journal={STEM CELLS}, publisher={Wiley}, author={Li, Tao-Sheng and Cheng, Ke and Lee, Shuo-Tsan and Matsushita, Satoshi and Davis, Darryl and Malliaras, Konstantinos and Zhang, Yiqiang and Matsushita, Noriko and Smith, Rachel Ruckdeschel and Marbán, Eduardo}, year={2010}, month={Nov}, pages={2088–2098} }
 @article{zhang_li_lee_wawrowsky_cheng_galang_malliaras_abraham_wang_marbán_2010, title={Dedifferentiation and Proliferation of Mammalian Cardiomyocytes}, volume={5}, ISSN={1932-6203}, url={http://dx.doi.org/10.1371/journal.pone.0012559}, DOI={10.1371/journal.pone.0012559}, abstractNote={It has long been thought that mammalian cardiomyocytes are terminally-differentiated and unable to proliferate. However, myocytes in more primitive animals such as zebrafish are able to dedifferentiate and proliferate to regenerate amputated cardiac muscle.Here we test the hypothesis that mature mammalian cardiomyocytes retain substantial cellular plasticity, including the ability to dedifferentiate, proliferate, and acquire progenitor cell phenotypes. Two complementary methods were used: 1) cardiomyocyte purification from rat hearts, and 2) genetic fate mapping in cardiac explants from bi-transgenic mice. Cardiomyocytes isolated from rodent hearts were purified by multiple centrifugation and Percoll gradient separation steps, and the purity verified by immunostaining and RT-PCR. Within days in culture, purified cardiomyocytes lost their characteristic electrophysiological properties and striations, flattened and began to divide, as confirmed by proliferation markers and BrdU incorporation. Many dedifferentiated cardiomyocytes went on to express the stem cell antigen c-kit, and the early cardiac transcription factors GATA4 and Nkx2.5. Underlying these changes, inhibitory cell cycle molecules were suppressed in myocyte-derived cells (MDCs), while microRNAs known to orchestrate proliferation and pluripotency increased dramatically. Some, but not all, MDCs self-organized into spheres and re-differentiated into myocytes and endothelial cells in vitro. Cell fate tracking of cardiomyocytes from 4-OH-Tamoxifen-treated double-transgenic MerCreMer/ZEG mouse hearts revealed that green fluorescent protein (GFP) continues to be expressed in dedifferentiated cardiomyocytes, two-thirds of which were also c-kit(+).Contradicting the prevailing view that they are terminally-differentiated, postnatal mammalian cardiomyocytes are instead capable of substantial plasticity. Dedifferentiation of myocytes facilitates proliferation and confers a degree of stemness, including the expression of c-kit and the capacity for multipotency.}, number={9}, journal={PLoS ONE}, publisher={Public Library of Science (PLoS)}, author={Zhang, Yiqiang and Li, Tao-Sheng and Lee, Shuo-Tsan and Wawrowsky, Kolja A. and Cheng, Ke and Galang, Giselle and Malliaras, Konstantinos and Abraham, M. Roselle and Wang, Charles and Marbán, Eduardo}, editor={Kowaltowski, Alicia J.Editor}, year={2010}, month={Sep}, pages={e12559} }
 @article{li_cheng_malliaras_matsushita_sun_marbán_zhang_marbán_2010, title={Expansion of human cardiac stem cells in physiological oxygen improves cell production efficiency and potency for myocardial repair}, volume={89}, ISSN={1755-3245 0008-6363}, url={http://dx.doi.org/10.1093/cvr/cvq251}, DOI={10.1093/cvr/cvq251}, abstractNote={the ex vivo expansion of cardiac stem cells from minimally invasive human heart biopsies yields tens of millions of cells within 3-4 weeks, but chromosomal abnormalities were frequently detected in preliminary production runs. Here we attempt to avoid aneuploidy and improve cell quality by expanding human cardiac stem cells in physiological low-oxygen (5% O(2)) conditions, rather than in traditional culture in a general CO(2) incubator (20% O(2)).human heart biopsies (n = 16) were divided and processed in parallel to expand cardiac stem cells under 5% or 20% O(2). Compared with 20% O(2), 5% O(2) culture doubled the cell production and markedly diminished the frequency of aneuploidy. Cells expanded in 5% O(2) showed lower intracellular levels of reactive oxygen species, less cell senescence, and higher resistance to oxidative stress than those grown in 20% O(2), although the expression of stem cell antigens and adhesion molecules was comparable between groups, as was the paracrine secretion of growth factors into conditioned media. In vivo, the implantation of 5% O(2) cells into infarcted hearts of mice resulted in greater cell engraftment and better functional recovery than with conventionally cultured cells.the expansion of human adult cardiac stem cells in low oxygen increased cell yield, and the resulting cells were superior by various key in vitro and in vivo metrics of cell quality. Physiological oxygen tensions in culture facilitate the ex vivo expansion of healthy, biologically potent stem cells.}, number={1}, journal={Cardiovascular Research}, publisher={Oxford University Press (OUP)}, author={Li, Tao-Sheng and Cheng, Ke and Malliaras, Konstantinos and Matsushita, Noriko and Sun, Baiming and Marbán, Linda and Zhang, Yiqiang and Marbán, Eduardo}, year={2010}, month={Jul}, pages={157–165} }
 @article{cheng_kisaalita_2010, title={Exploring cellular adhesion and differentiation in a micro-/nano-hybrid polymer scaffold}, volume={26}, ISSN={8756-7938 1520-6033}, url={http://dx.doi.org/10.1002/btpr.391}, DOI={10.1002/btpr.391}, abstractNote={Polymer scaffolds play an important role in three dimensional (3-D) cell culture and tissue engineering. To best mimic the archiecture of natural extracellular matrix (ECM), a nano-fibrous and micro-porous combined (NFMP) scaffold was fabricated by combining phase separation and particulate leaching techniques. The NFMP scaffold possesses architectural features at two levels, including the micro-scale pores and nano-scale fibers. To evaluate the advantages of micro/nano combination, control scaffolds with only micro-pores or nano-fibers were fabricated. Cell grown in NFMP and control scaffolds were characterized with respect to morphology, proliferation rate, diffentiation and adhesion. The NFMP scaffold combined the advantages of micro- and nano-scale structures. The NFMP scaffold nano-fibers promoted neural differentiation and induced "3-D matrix adhesion", while the NFMP scaffold micro-pores facilitated cell infiltration. This study represents a systematic comparison of cellular activities on micro-only, nano-only and micro/nano combined scaffolds, and demonstrates the unique advantages of the later.}, number={3}, journal={Biotechnology Progress}, publisher={Wiley}, author={Cheng, Ke and Kisaalita, William S.}, year={2010}, month={Mar}, pages={838–846} }
 @article{marbán eduardo_cheng_2010, title={Heart to Heart}, volume={121}, ISSN={0009-7322 1524-4539}, url={http://dx.doi.org/10.1161/circulationaha.110.952580}, DOI={10.1161/circulationaha.110.952580}, abstractNote={The notion of cell transplantation into the heart as a means of reversing ischemic injury is now nearly a decade old. The first clinical application of bone marrow mononuclear cells (BMCs) for myocardial infarction was in 2001,1 presumably motivated at least in part by the premise that BMCs injected into the heart can directly regenerate new, functional myocardium.2 Although subsequent investigators questioned the ability of BMCs to transdifferentiate into cardiomyocytes3,4 (but in all fairness, others did support the idea5,6), the horse was out of the barn, and the treatments continued apace. Fortunately, injection of autologous BMCs as adjunctive treatment for convalescent myocardial infarction has proven to be remarkably safe.7–9 Although the overall efficacy is modest, certain subgroups (particularly those with large functional deficits at baseline) do experience clinically meaningful increments in ejection fraction.10,11 A related consideration arises in the choice of cell type to transplant. BMCs, although easy to harvest, are almost certainly not the best candidate cells for cardiomyoplasty, because they are not specialized to regrow normal healthy heart muscle. An attractive alternative arose with the recognition that the adult heart contains its own reservoir of progenitor cells,12–15 some of which express the stem cell antigen c-kit.12,14 Such cardiac progenitor cells (CPCs) presumably function physiologically to mediate a low basal turnover rate of cardiomyocytes in the adult heart16 but may be expanded and exploited iatrogenically for more focused (and, mechanistically, more rational) benefit than may be possible with BMCs. When injected into the injured heart, CPCs increase tissue viability12,14,17–20 and improve ventricular function.12,14,17,20

Articles see p 1992 and p 2001 

Ironically, we are now less certain about the mechanism of cell therapy than we thought we were a decade ago, when it seemed that direct regeneration of tissue …}, number={18}, journal={Circulation}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Marbán Eduardo and Cheng, Ke}, year={2010}, month={May}, pages={1981–1984} }
 @article{cheng_li_malliaras_davis_zhang_marbán eduardo_2010, title={Magnetic Targeting Enhances Engraftment and Functional Benefit of Iron-Labeled Cardiosphere-Derived Cells in Myocardial Infarction}, volume={106}, ISSN={0009-7330 1524-4571}, url={http://dx.doi.org/10.1161/circresaha.109.212589}, DOI={10.1161/circresaha.109.212589}, abstractNote={Rationale : The success of cardiac stem cell therapies is limited by low cell retention, due at least in part to washout via coronary veins. Objective : We sought to counter the efflux of transplanted cells by rendering them magnetically responsive and imposing an external magnetic field on the heart during and immediately after injection. Methods and Results : Cardiosphere-derived cells (CDCs) were labeled with superparamagnetic microspheres (SPMs). In vitro studies revealed that cell viability and function were minimally affected by SPM labeling. SPM-labeled rat CDCs were injected intramyocardially, with and without a superimposed magnet. With magnetic targeting, cells were visibly attracted toward the magnet and accumulated around the ischemic zone. In contrast, the majority of nontargeted cells washed out immediately after injection. Fluorescence imaging revealed more retention of transplanted cells in the heart, and less migration into other organs, in the magnetically targeted group. Quantitative PCR confirmed that magnetic targeting enhanced cell retention (at 24 hours) and engraftment (at 3 weeks) in the recipient hearts by ≈3-fold compared to nontargeted cells. Morphometric analysis revealed maximal attenuation of left ventricular remodeling, and echocardiography showed the greatest functional improvement, in the magnetic targeting group. Histologically, more engrafted cells were evident with magnetic targeting, but there was no incremental inflammation. Conclusions : Magnetic targeting enhances cell retention, engraftment and functional benefit. This novel method to improve cell therapy outcomes offers the potential for rapid translation into clinical applications.}, number={10}, journal={Circulation Research}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Cheng, Ke and Li, Tao-Sheng and Malliaras, Konstantinos and Davis, Darryl R. and Zhang, Yiqiang and Marbán Eduardo}, year={2010}, month={May}, pages={1570–1581} }
 @article{davis_zhang_smith_cheng_terrovitis_malliaras_li_white_makkar_marbán_2009, title={Validation of the Cardiosphere Method to Culture Cardiac Progenitor Cells from Myocardial Tissue}, volume={4}, ISSN={1932-6203}, url={http://dx.doi.org/10.1371/journal.pone.0007195}, DOI={10.1371/journal.pone.0007195}, abstractNote={At least four laboratories have shown that endogenous cardiac progenitor cells (CPCs) can be grown directly from adult heart tissue in primary culture, as cardiospheres or their progeny (cardiosphere-derived cells, CDCs). Indeed, CDCs are already being tested in a clinical trial for cardiac regeneration. Nevertheless, the validity of the cardiosphere strategy to generate CPCs has been called into question by reports based on variant methods. In those reports, cardiospheres are argued to be cardiomyogenic only because of retained cardiomyocytes, and stem cell activity has been proposed to reflect hematological contamination. We use a variety of approaches (including genetic lineage tracing) to show that neither artifact is applicable to cardiospheres and CDCs grown using established methods, and we further document the stem cell characteristics (namely, clonogenicity and multilineage potential) of CDCs.CPCs were expanded from human endomyocardial biopsies (n = 160), adult bi-transgenic MerCreMer-Z/EG mice (n = 6), adult C57BL/6 mice (n = 18), adult GFP(+) C57BL/6 transgenic mice (n = 3), Yucatan mini pigs (n = 67), adult SCID beige mice (n = 8), and adult Wistar-Kyoto rats (n = 80). Cellular yield was enhanced by collagenase digestion and process standardization; yield was reduced in altered media and in specific animal strains. Heparinization/retrograde organ perfusion did not alter the ability to generate outgrowth from myocardial sample. The initial outgrowth from myocardial samples was enriched for sub-populations of CPCs (c-Kit(+)), endothelial cells (CD31(+), CD34(+)), and mesenchymal cells (CD90(+)). Lineage tracing using MerCreMer-Z/EG transgenic mice revealed that the presence of cardiomyocytes in the cellular outgrowth is not required for the generation of CPCs. Rat CDCs are shown to be clonogenic, and cloned CDCs exhibit spontaneous multineage potential.This study demonstrates that direct culture and expansion of CPCs from myocardial tissue is simple, straightforward, and reproducible when appropriate techniques are used.}, number={9}, journal={PLoS ONE}, publisher={Public Library of Science (PLoS)}, author={Davis, Darryl R. and Zhang, Yiqiang and Smith, Rachel R. and Cheng, Ke and Terrovitis, John and Malliaras, Konstantinos and Li, Tao-Sheng and White, Anthony and Makkar, Raj and Marbán, Eduardo}, editor={Leri, AnnarosaEditor}, year={2009}, month={Sep}, pages={e7195} }
 @article{cheng_lai_kisaalita_2008, title={ENStem-A human neural progenitors cultured in 3D polystyrene scaffolds for high physiological relevance}, volume={3}, journal={Cellutions}, author={Cheng, K. and Lai, Y. and Kisaalita, W.S.}, year={2008}, pages={4–6} }
 @article{lai_wang_cheng_kisaalita_2008, title={Taking Cell Culture in Drug Discovery to the Third Dimension - A Patent Review}, volume={1}, ISSN={1874-7647}, url={http://dx.doi.org/10.2174/1874764710801020103}, DOI={10.2174/1874764710801020103}, number={2}, journal={Recent Patents on Biomedical Engineeringe}, publisher={Bentham Science Publishers Ltd.}, author={Lai, Yinzhi and Wang, Lina and Cheng, Ke and Kisaalita, William}, year={2008}, month={Jun}, pages={103–115} }
 @article{cheng_lai_kisaalita_2008, title={Three-dimensional polymer scaffolds for high throughput cell-based assay systems}, volume={29}, ISSN={0142-9612}, url={http://dx.doi.org/10.1016/j.biomaterials.2008.03.015}, DOI={10.1016/j.biomaterials.2008.03.015}, abstractNote={Many whole cell-based assays in use today rely on flat, two-dimensional (2D) glass or plastic substrates that may not produce results characteristic of in vivo conditions. In this study, a three-dimensional (3D) cell-based assay platform was established by integrating 3D synthetic polymer scaffolds with standard cell culture dishes and multi-well plates. This technology can be used to feasibly modify any traditional 2D cell-based assay vessels for 3D cell-based assay with currently used high throughput screening (HTS) systems. We examined neural stem (NS) cells' growth profile, morphology, cell-matrix interaction, gene expression and voltage gated calcium channel (VGCC) functionality of this novel 3D assay platform. Our results showed that unlike the NS cells cultured on traditional 2D planar surfaces, cells in 3D scaffolds are more physiologically relevant with respect to in vivo characteristics exhibited by in-vivo surrogates such as neural spheres. This new biomimetic cell-based assay platform may provide a broadly applicable 3D cell-based system for use in drug discovery programs and other research fields.}, number={18}, journal={Biomaterials}, publisher={Elsevier BV}, author={Cheng, Ke and Lai, Yinzhi and Kisaalita, William S.}, year={2008}, month={Jun}, pages={2802–2812} }
 @article{hu_lu_cheng_liu_2003, title={Application potentials of on-line near infrared spectroscopy technology in manufacturing of traditional chinese medicine}, volume={28}, journal={China Journal of Chinese Materia Medica}, author={Hu, G.-G. and Lu, X.-Y. and Cheng, K. and Liu, D.-Q.}, year={2003}, pages={1117–1119} }