Abstract 4147671: Exosomes from Induced Pluripotent Stem Cell-Derived Cardiomyocytes, miRNA, and siRNA Restore the Porcine Chronic Myocardial Injury Model

Introduction: Heart failure is the leading cause of hospital admission in the U.S. We previously demonstrated that exosomes (Exo) from induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) significantly restored murine peri-infarct region. Furthermore, we delineated that miR20/92/363 (CORE miRNA) in Exo activated iCM proliferation and restored the injured myocardium by derepressing the Notch3 pathway. However, the optimal pre-clinical method to target the Notch3 pathway effectively through Exo, miRNA, and siRNA remains to be assessed. Hypothesis: Exo are the most effective biologic to target the Notch3 pathway to improve chronic porcine heart failure model by cardiomyocyte proliferation. Methods: iPSCs were differentiated into iCMs. Exo were isolated from the iCM culture media. Yorkshire pigs were subjected to ischemia-reperfusion injury via balloon occlusion of the left descending artery for one hour. One month later, chronic heart failure model was developed, and percutaneous catheter system (Biocardia, Inc) delivered 10 11 Exo, 4200 µg of CORE miRNA, or 4200 µg of siNotch3 into the porcine peri-infarct region. MRI and transcriptomic analyses evaluated the function, morphology and genomic changes in the injured porcine myocardium. Results: Significant improvement in mean absolute change in LVEF when compared to PBS (control, n=6) was achieved in CORE miRNA (n=5), iCM-Exo (n=5), and siNotch 3 (n=4) treatments: 5.89 ± 1.53***, 7.07 ±3.59***, and 4.73 ± 3.17** respectively (PBS -3.55 ± 3.27, mean±SD, **p<0.01, ***p<0.001). LV end systolic volume was significantly reduced in both CORE miRNA and iCM-Exo treatment groups. Transcriptomic analysis of the porcine myocardium was performed to assess cell proliferation and metabolism. Conclusion: All biologics were effective in repairing the porcine myocardium after chronic myocardial injury. iCM-Exo showed the highest functional restoration. Dose-response study is ongoing to optimize the restorative effects.