Co-transplantation of hiPSC-Derived Mesenchymal Stem Cells and Cardiomyocytes Enhances Cardiac Regeneration After Myocardial Infarction

Nearly a billion cardiomyocytes (CMs) are lost during an acute myocardial infarction (AMI) which eventually leads to heart failure. While most conventional treatments for AMI are only palliative, transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs) has been shown to improve cardiac function. However, the use of hiPSC-CMs has been limited by their poor engraftment and survival in the ischemic microenvironment post-MI. Since hiPSC-derived mesenchymal stem cells (hiPSC-MSCs) have been shown to promote cardioprotection via paracrine mechanisms, we hypothesized that co-transplantation of hiPSC-CMs and hiPSC-MSCs in ischemic hearts may improve cardioprotection and engraftment of transplanted hiPSC-CMs. We co-cultured hiPSC-CMs and hiPSC-MSCs and assessed the changes in morphology (TEM, ICC), gene expression (qRT-PCR), and cardiac function (MEA, and calcium transients) under normoxia and hypoxia (1% O 2 ). We observed increased maturation (elevated β-MHC expression, higher amplitude of contraction, increased sarcomere alignment) in hiPSC-CMs cultured in hiPSC-MSC derived conditioned medium. On the other hand, we observed enhanced survival (TUNEL assay) of hiPSC-CMs co-cultured with hiPSC-CMs following hypoxic insult. Additionally, following intramyocardial transplantation of (a) hiPSC-CMs, (b) hiPSC-MSCs or (c) hiPSC-CMs + hiPSC-MSCs (3:1) in a mouse MI model, we observed improved cardiac function, LVEF (p < 0.01) and FS (p<0.01) in all three groups as compared to MI-only group. We also observed effcient hiPSC-CM engraftment (human-specific markers, cTnT and HNA) in both hiPSC-CM-only and hiPSC-CM + hiPSC-MSC groups at 4-weeks post-MI. Furthermore, we observed increased angiogenesis (α-SMA, CD31) in the hiPSC-MSC-only and hiPSC-CM + hiPSC-MSC groups, as compared to control and hiPSC-CM-only groups. Taken together, our results showed that co-transplantation of hiPSC-MSCs and hiPSC-CMs can be explored as a novel combinatorial therapy for myocardial regeneration post-MI. Funding: AHA postdoctoral fellowship to DS (916599), and NIH RO1 HLHL136232 and OSU Start-up funds to MK. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.