Andrew R. Kompa, David W. Greening, Jarmon G. Lees, Anne M. Kong, Jonathon Cross, Ashley Nowland, Ren J. Phang, Saba Naghipour, Yali Deng, Jack R. T. Darby, Lina Mariana, Cameron Kos, Tanya Hall, Andrew Newcomb, James J.H. Chong, Rebecca H. Ritchie, Janna L. Morrison, Klearchos K. Papas, Kilian Kelly, Derek J. Hausenloy, Thomas Loudovaris, Shiang Y. Lim
BACKGROUND: Effective long-term strategies to protect the ischaemic heart remain a significant challenge. Mesenchymal stromal cells (MSCs) offer therapeutic potential primarily through their secretome, a bioactive factor-rich milieu with broad beneficial effects. However, existing delivery methods have not demonstrated sustained cardioprotection. The objective of this study was to evaluate a clinically translatable approach for sustained MSC-secretome delivery to achieve long-term cardioprotection. METHODS: Cymerus MSCs, derived from human induced pluripotent stem cells (iPSCs), were encapsulated in a Procyon immunoisolation device and implanted subcutaneously in adult Sprague Dawley rats with chronic myocardial ischaemia-reperfusion injury. A human iPSC-derived engineered cardiac microtissue model was used to simulate ischaemia-reperfusion injury and assess cardioprotective effects in a human context. Proteomic analysis was performed to characterize adaptive changes in MSCs and their secretome post-implantation. RESULTS: The MSC-loaded Procyon device significantly improved cardiac function and reduced adverse left ventricular remodelling over 12 weeks in both young and middle-aged, male and female rats. The encapsulated MSCs remained viable and retained the ability to release therapeutic secretome at 12 weeks post-implantation. In vitro, the MSC secretome protected human engineered cardiac microtissues from simulated ischaemia-reperfusion injury by restoring contractile function, improving cell viability, and reducing oxidative stress. Proteomic profiling of encapsulated MSC identified 179 unique cellular proteins post-implantation, associated with adaptive immune and inflammatory responses as well as wound healing. MSC secretome profiling revealed increased protein diversity associated with tissue repair and immune regulation, suggesting MSCs undergo an adaptive response to ischaemic conditions. CONCLUSION: This translational study highlights a clinically viable, minimally invasive method for sustained cardioprotection, harnessing the MSC secretome to address a pivotal gap in current treatments for ischaemic heart disease.