Andrew R Kompa1,2, David W Greening3,4, Anne M Kong5, Paul J McMillan6, Haoyun Fang3, Ritika Saxena5,7, Raymond C B Wong1,8,9, Jarmon G Lees1,5, Priyadharshini Sivakumaran5, Andrew E Newcomb10, Bakhos A Tannous11,12, Cameron Kos13, Lina Mariana13, Thomas Loudovaris13, Derek J Hausenloy14,15,16,17,18, Shiang Y Lim1,5. 1. Departments of Medicine and Surgery, University of Melbourne, Melbourne, VIC, Australia. 2. Department of Epidemiology and Preventive Medicine, Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia. 3. Molecular Proteomics, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. 4. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia. 5. O'Brien Institute Department, St Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, VIC 3065, Australia. 6. Department of Biochemistry and Molecular Biology, Biological Optical Microscopy Platform, University of Melbourne, Melbourne, VIC, Australia. 7. School of Life and Environmental Sciences, Faculty of Science, Deakin University, Burwood, VIC, Australia. 8. Cellular Reprogramming Unit, Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia. 9. Shenzhen Eye Hospital, Shenzhen University School of Medicine, Shenzhen, China. 10. Department of Cardiothoracic Surgery, St Vincent's Hospital Melbourne, Melbourne, VIC, Australia. 11. Department of Neurology and Pathology, Massachusetts General Hospital, Charlestown, MA, USA. 12. Program in Neuroscience, Harvard Medical School, Boston, MA, USA. 13. O'Brien Institute Department & Immunology & Diabetes Unit, St Vincent's Institute of Medical Research, VIC, Australia. 14. Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore. 15. National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore. 16. The Hatter Cardiovascular Institute, University College London, London, UK. 17. Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taichung, Taiwan. 18. Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.
Abstract
AIMS: To establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant cardioreparative outcomes in the setting of myocardial infarction. METHODS AND RESULTS: Rats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1 × 106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs. CONCLUSIONS: Subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: To establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant cardioreparative outcomes in the setting of myocardial infarction. METHODS AND RESULTS: Rats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1 × 106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs. CONCLUSIONS: Subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy. Published on behalf of the European Society of Cardiology. All rights reserved.
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