@article{wang_li_shi_zhu_hu_dinh_cheng_2023, title={A SARS-CoV-2 and influenza double hit vaccine based on RBD-conjugated inactivated influenza A virus}, volume={9}, ISSN={["2375-2548"]}, url={https://doi.org/10.1126/sciadv.abo4100}, DOI={10.1126/sciadv.abo4100}, abstractNote={The circulating flu viruses merging with the ongoing COVID-19 pandemic raises a more severe threat that promotes the infectivity of SARS-CoV-2 associated with higher mortality rates. Here, we conjugated recombinant receptor binding domain (RBD) of SARS-CoV-2 spike protein onto inactivated influenza A virus (Flu) to develop a SARS-CoV-2 virus-like particle (VLP) vaccine with two-hit protection. This double-hit vaccine (Flu-RBD) not only induced protective immunities against SARS-CoV-2 but also remained functional as a flu vaccine. The Flu core improved the retention and distribution of Flu-RBD vaccine in the draining lymph nodes, with enhanced immunogenicity. In a hamster model of live SARS-CoV-2 infection, two doses of Flu-RBD efficiently protected animals against viral infection. Furthermore, Flu-RBD VLP elicited a strong neutralization activity against both SARS-CoV-2 Delta pseudovirus and wild-type influenza A H1N1 inactivated virus in mice. Overall, the Flu-RBD VLP vaccine is a promising candidate for combating COVID-19, influenza A, and coinfection.}, number={25}, journal={SCIENCE ADVANCES}, author={Wang, Zhenzhen and Li, Zhenhua and Shi, Weiwei and Zhu, Dashuai and Hu, Shiqi and Dinh, Phuong-Uyen C. and Cheng, Ke}, year={2023}, month={Jun} }
 @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. An inhalable virus-like-particle consisting of exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain is stable at room temperature and elicits systemic and mucosal immune responses in small animals.}, 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{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={•Lung extracellular vesicles (Lung-Exos) can package mRNA and protein drugs•Lung-Exos are deliverable through nebulization and dry powder inhalation•Dry powder Lung-Exos are room-temperature stable up to 28 days•Drug-loaded Lung-Exos can serve as an inhalable vaccine to illicit immune responses Research in extracellular vesicles (EVs) is important to the field of translational medicine to develop therapeutics that are limited by poor cellular targeting and efficacy. The biological composition of EVs can be exploited as drug-delivery vehicles that may be engineered for cellular targeting or eliciting specific immune responses through their functions in membrane trafficking and cellular signaling. With the molecular composition of EVs varying depending on their parent-cell origin, the derivation of EVs can further refine nanomedicine by utilizing nanoparticles that are recognized by specific cellular microenvironments. EVs are found in almost all biological fluids, opening the application of EVs as tailored drug-delivery vesicles to a wide range of diseases. 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. 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. 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Exosome therapeutics for COVID-19 and respiratory viruses.View. 2021; : 20200186https://doi.org/10.1002/VIW.20200186Crossref Google Scholar Our group has demonstrated the lung regenerative abilities of human lung spheroid cells (LSCs)8Cores J. Hensley M.T. Kinlaw K. Rikard S.M. Dinh P.-U. Paudel D. Tang J. Vandergriff A.C. Allen T.A. Li Y. et al.Safety and efficacy of allogeneic lung spheroid cells in a mismatched rat model of pulmonary fibrosis.Stem Cells Transl. Med. 2017; 6: 1905-1916https://doi.org/10.1002/sctm.16-0374Crossref PubMed Scopus (18) Google Scholar,9Cores J. Dinh P.U.C. Hensley T. Adler K.B. Lobo L.J. Cheng K. A pre- investigational new drug study of lung spheroid cell therapy for treating pulmonary fibrosis.Stem Cells Transl. Med. 2020; 9: 786-798https://doi.org/10.1002/sctm.19-0167Crossref PubMed Scopus (5) Google Scholar in rodent models of idiopathic pulmonary fibrosis (IPF), and their safety and efficacy are being tested in a human clinical trial (HALT-IPF, ClinicialTrials.gov: NCT04262167). LSCs and their secreted exosomes (lung-derived extracellular vesicles [Lung-Exos]) have regenerative abilities in IPF models13Dinh P.-U.C. Paudel D. Brochu H. Popowski K.D. Gracieux M.C. Cores J. Huang K. Hensley M.T. Harrell E. Vandergriff A.C. et al.Inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis.Nat. Commun. 2020; 11: 1064https://doi.org/10.1038/s41467-020-14344-7Crossref PubMed Scopus (127) Google Scholar and protective abilities against COVID-19 as decoys.32Li Z. Wang Z. Dinh P.-U.C. Zhu D. Popowski K.D. Lutz H. Hu S. Lewis M.G. Cook A. Andersen H. et al.Cell-mimicking nanodecoys neutralize SARS-CoV-2 and mitigate lung injury in a non-human primate model of COVID-19.Nat. Nanotechnol. 2021; 16: 942-951https://doi.org/10.1038/s41565-021-00923-2Crossref PubMed Scopus (43) Google Scholar In both disease models, Lung-Exos maintained therapeutic efficacy through jet-nebulization administration, demonstrating the ability of Lung-Exos to function as an inhalable drug-delivery and vaccine vehicle. Additionally, exosomes can be synthetically supplemented to enhance cellular targeting and therapeutic efficacy.33Hutcheson J.D. Aikawa E. Extracellular vesicles in cardiovascular homeostasis and disease.Curr. Opin. Cardiol. 2018; 33: 290-297https://doi.org/10.1097/HCO.0000000000000510Crossref PubMed Scopus (29) Google Scholar, 34Li S.p. Lin Z.x. Jiang X. Yu X.y. Yu X. Exosomal cargo-loading and synthetic exosome-mimics as potential therapeutic tools.Acta Pharmacol. 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Paudel D. Brochu H. Popowski K.D. Gracieux M.C. Cores J. Huang K. Hensley M.T. Harrell E. Vandergriff A.C. et al.Inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis.Nat. Commun. 2020; 11: 1064https://doi.org/10.1038/s41467-020-14344-7Crossref PubMed Scopus (127) Google Scholar,37Zhang D. Lee H. Wang X. Rai A. Groot M. Jin Y. Exosome-Mediated small RNA delivery: a novel therapeutic approach for inflammatory lung responses.Mol. Ther. 2018; 26: 2119-2130https://doi.org/10.1016/j.ymthe.2018.06.007Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar the distribution and retention of exosome particles in the lung have yet to be determined. Drug effectiveness depends on proper deposition of particles within the respirable fraction, requiring optimized nanoparticle formulation. In this study, we sought to elucidate the biodistribution of lung-derived exosomes upon nebulization, baselined to liposomes (Lipos) as a commercial standard. Furthermore, to provide a room-temperature-stable product, we formulated exosomes as a lyophilized dry powder to investigate their stability and inhaled biodistribution in the lung of both the mouse and African green monkey (AGM). The parent-cell signature of Lung-Exos may suggest that they are naturally optimized for the distribution and retention within the lung, which may allow them to bypass pulmonary clearance more efficiently than Lipos or exosomes derived from other cell types. Through this enhanced pulmonary bioavailability, we hypothesize that lung-derived exosomes elicit greater therapeutic responses for pulmonary diseases and serve as a customizable drug-delivery vehicle for room-temperature-stable inhaled mRNA therapeutics.ResultsExosome distribution in the bronchioles and parenchyma are superior to that of synthetic nanoparticlesRed fluorescent protein (RFP)-labeled lung-derived exosomes (RFP-Exos) and Lipos (RFP-Lipos) were fabricated to generate trackable nanoparticles for biodistribution analysis in the murine lung after inhalation treatment through three-dimensional (3D) imaging (Figure 1A ). The nanoparticles were characterized by transmission electron microscopy (TEM), confirming that the isolation of exosomes and Lipos did not disrupt vesicular membrane integrity (Figure 1B). RFP loading was verified by immunoblotting (Figure 1C). When co-cultured with lung parenchymal cells, RFP-Exo had a 6.7-fold increase in cellular uptake and RFP protein expression compared with cells cultured with RFP-Lipo (Figures 1D and 1E). Next, the biodistribution of nanoparticles in vivo were evaluated through light-sheet fluorescence microscopy (LSFM) (Figure 1F). Healthy mice received a single dose of RFP-Exos or RFP-Lipos via nebulization and were sacrificed after 24 h. LSFM imaging confirmed nanoparticle delivery to the conducting airways and the deep lung, with an accumulation of RFP-Exos in the upper pulmonary regions (Videos S1 and S2). Quantification of nanoparticle delivery to the whole lung demonstrated a 3.7-fold improvement in RFP-Exo retention and uptake compared with RFP-Lipo (Figure 1G). Segmentation of the lung into bronchial and parenchymal regions revealed 2.9- and 3.8-fold improvements in RFP-Exo retention and uptake, respectively, compared with RFP-Lipo (Figure 1H). Flow cytometry analysis in lung parenchymal cells (Figure 1I) and in the murine lung following nebulization (Figure 1J) confirmed greater cellular uptake of RFP-Exos than RFP-Lipos. The drug-loading capabilities of lung-derived exosomes (Lung-Exos and Lipos were expanded by loading GFP-encoding mRNA to evaluate nanoparticle mRNA uptake. Lung parenchymal cells that received GFP-Exos demonstrated more rapid internalization of exosomal mRNA than liposomal mRNA (Figure S1). These data confirm that our nanoparticle labeling system maintains nanoparticle integrity while delivering functional and translatable cargo after jet nebulization. In vitro and in vivo analyses suggest superior retention and cellular uptake of exosomes over Lipos in the lung. The native lung signature of lung-derived exosomes may enhance pulmonary bioavailability, resulting in an optimized nanoparticle vesicle for drug delivery for respiratory diseases.eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiIyZDE5ZTI0ODk4NDRkYTFhYjJlNGUzMWEwMGE4OTEyYyIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjY5OTY2NjUwfQ.ZP_2__aVFlfG_3XKl06osGFI0GeEXb27ElTxZ-KGGM8IcSO676pqZKF6h65jz0cnnYuojIwvoPOnatMAd9qqR65EtMzNhGLYU-TdT2hEgjFIUL9AatnXvIyrTXEJt4Orap9iWn8eBBxr63jGbLdLvzqnA2A05saBmcwbPhbN3bVzqdWYJQCLOpzv6z8Yi-0i3xtJfwEmLHgdsvSLgQt8vnGKzY4IUA9jBXCdfho1Cp5PVg3eCXd0p9bQo-Df_q9s-Ghg1957V4C1OlRDoKdNdXo62FKjOcdLZPrCnVgzDNqmk_IPHTSkzr3rdFCG41UJVBXHBYkJMpXnhOvsDyhoXw Download .mp4 (30.4 MB) Help with .mp4 files Video S1. Biodistribution of nebulized RFP-Exos in mouse lungsLSFM imaging and 3D rendering and animation by Imaris confirms labeled exosome distribution throughout the lung. Tissue autofluorescence allows for morphological segmentation of bronchioles and parenchyma to quantify exosome distribution.eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJiNTYzZTFmZDNiYjJiOTQzMWQyMDAwODQzYzA2MDcxNCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjY5OTY2NjUwfQ.rrwycH66nt21uB8nXcVXQaa02xcRy_2vJlbQsIigymt2QlJ24qCloQxenvyl4rqzmA9WIpCs6ZdvZ5yRY5FWlu-j2SfO4Sl8lcL2Xz3jrbu8PU-Ge_avejxOWdeaYEEEGIbmAWmXlVHWH2p6_LlFpfPB-j4E-KTapjf5CHzT4rGRom3mXroj6OiJkAkRl3ylnmxTdNaQDUbtDr2dJvIYzLCX_8TUNx9a7L4Rz-65ZWZD_ZXLADu_bgTFdnNOGodGmEY-9NZhPBqraOljjTPxzbe4TJJOttzGsmAySGpVDMWGFGcStxkuif_tgwujLF5wcLU1o-KQtk8eosKrcuRuxA Download .mp4 (38.39 MB) Help with .mp4 files Video S2. Biodistribution of nebulized RFP-Lipos in mouse lungsLSFM imaging and 3D rendering and animation by Imaris confirms labeled liposome distribution throughout the lung. Tissue autofluorescence allows for morphological segmentation of bronchioles and parenchyma to quantify liposome distribution.Lung-derived exosomes efficiently penetrate mucusDelivery of inhaled therapeutics must penetrate the lung’s protective mucus lining to provide pulmonary bioavailability. Lung-Exos were compared against human embryonic kidney (HEK)-derived exosomes (HEK-Exos) and Lipos to determine if nanoparticle derivation affected mucus penetrance. To test this, we used a model of the human airway at the air-liquid interface (Figure S2A), with human mucus-secreting bronchial epithelial cells lining the transwell membrane and human lung parenchymal cells lining the well (Figure S2B). Immunostaining confirmed the mucus lining in the transwell membrane and delivery of DiD-labeled nanoparticles (Figure S2C). Quantification of nanoparticle penetrance into the wells revealed the greatest uptake of Lung-Exos (Figure S2D), with the highest percentage of cellular uptake by lung parenchymal cells (Figure S2E) by 24 h. Likewise, Lung-Exos had the least entrapment by the mucus-lined membrane (Figure S2F) and the lowest percentage of cellular uptake by bronchial epithelial cells (Figure S2G). These data confirm mucus penetrance of the nanoparticles and suggest that Lung-Exos can most efficiently evade mucoadhesion, overcoming the lung’s natural defense mechanism and allowing for greater parenchymal bioavailability.Lung-derived exosomes are room-temperature stable and distributable in dry powder formulation in the murine lungRoom-temperature formulation of therapeutics circumvents major limitations in traditional IM vaccine delivery: deep-freezing storage, healthcare professional administration, and reduced patient compliance. Therefore, we reformulated our liquid nanoparticle suspensions into dry, lyophilized powder for dry powder inhalation (DPI) administration. We verified the efficacy and stability of room-temperature lyophilized Lung-Exos up to 28 days in the murine lung (Figure 2A ). To verify dry powder nanoparticle stability and shelf life, lyophilized nanoparticle cargo leakage was tested by an enzyme-linked immunosorbent assay (ELISA), where nanoparticles had less than 2.4% of total pg/mL cargo leakage at day 28 of room-temperature storage (Figures 2B and S3). Next, the morphology of nanoparticles was evaluated across their fresh and lyophilized formulations, as well as lyophilized powder reconstituted in water (reconstituted), to mimic rehydration of dry powder by saliva and mucus. TEM (Figures 2E and S4) and atomic force microscopy (AFM) verified that reformulation and rehydration did not affect nanoparticle membrane integrity (Figures 2C and S5) but did affect size distributions through clumping (Figure S6–S8). Lyophilization increased nanoparticle height and diameter (Figure 2D) but remained as small respiratory droplets upon reconstitution. Across all formulations, the nanoparticle diameters are approximately 10-fold larger, which may be explained by tip dilation38Wong C. West P.E. Olson K.S. Mecartney M.L. Starostina N. Tip dilation and AFM capabilities in the characterization of nanoparticles.JOM. 2007; 59: 12-16https://doi.org/10.1007/s11837-007-0003-xCrossref Scopus (40) Google Scholar that reports larger lateral dimensions than 2D analysis such as through TEM.39Eaton P. Quaresma P. Soares C. Neves C. de Almeida M.P. Pereira E. West P. A direct comparison of experimental methods to measure dimensions of synthetic nanoparticles.Ultramicroscopy. 2017; 182: 179-190https://doi.org/10.1016/j.ultramic.2017.07.001Crossref PubMed Scopus (164) Google Scholar Cross-section measurement curves demonstrate a restoration of membrane “smoothness” in reconstituted nanoparticles, mimicking fresh formulation (Figure S9). Next, we delivered the lyophilized Lung-Exos via DPI, where ex vivo images (Figure 2F) of mouse lungs who received fresh (fresh lyophilized) and 28-day-old (28-day lyophilized) dry powder Lung-Exos had no significant difference in exosomal mRNA and protein distribution (Figure 2G). mRNA activity showed greater variability at it 28-day-old state, but protein activity remained more stable.Figure 2Stability and distribution of lung-derived exosomes in dry powder formulation in the murine lungShow full caption(A) Schematic of mRNA and protein-loaded lung-derived exosome lyophilization, encapsulation, rodent DPI administration, and ex vivo histology. Created with BioRender.com.(B) Heatmaps of RFP leakage from Lung-Exos, HEK-Exos, and Lipos detected by ELISA; n = 2 per group.(C) Representative AFM height (I), amplitude (II), and phase (III) images of Lung-Exos; scale bar: 50 nm.(D) Quantification of the height and diameter of Lung-Exos, HEK-Exos, and Lipos from AFM images; n = 9 per group; data are represented as mean ± standard deviation.(E) TEM images of Lung-Exos at frozen (Frozen) or room (Lyophilized) temperatures; scale bar: 50 nm.(F) Ex vivo images of mouse lungs that received fresh lyophilized (0 days) and 28-day-old lyophilized Lung-Exos via dry powder inhalation after 24 h.(G) Quantification of the integrated density of GFP and RFP fluorescence in ex vivo mouse lungs 24 h after fresh (Fresh-Lyos) and 28-day-old (28-Day Lyos) dry powder inhalation; n = 3 per group; data are represented as mean ± standard deviation.(H) Quantification of the integrated density of GFP and RFP fluorescence in ex vivo mouse lungs 24 h after nebulization and fresh (Fresh-Lyos) dry powder inhalation; n = 3 per group; data are represented as mean ± standard deviation.(I) Quantification of the integrated density of GFP and RFP fluorescence in ex vivo mouse lungs 24 h after nebulization and 28-day-old (28-Day Lyos) dry powder inhalation; n = 3 per group; data are represented as mean ± standard deviation.View Large}, 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} }
 @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{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{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{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{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{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{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{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_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={Abstract 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{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} }