@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={AbstractIdiopathic 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{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_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={http://dx.doi.org/10.1038/s41551-017-0182-x}, 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. The attachment of platelet nanovesicles to the surface of cardiac stem cells increases the retention of the cells delivered to the heart and reduces infarct size in rat and pig models of acute myocardial infarction.}, number={1}, journal={Nature Biomedical Engineering}, publisher={Springer Science and Business Media LLC}, 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{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={AbstractCardiosphere‐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{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={AbstractStem 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{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={AbstractThe 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} }
 @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}, abstractNote={Cardiomyocytes are frequently used for in vitro models for cardiac research. The isolation of cells is time-consuming and, due to the cells limited proliferative abilities, must be performed frequently. To reduce the time requirements and the impact on research animals, we describe a method for cryopreserving neonatal rat cardiomyocytes (NRCMs), and subsequently thawing them for use in assays.}, 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={Aims 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. Methods and Results 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. Conclusion 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{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} }