Abstract Body (Do not enter title and authors here): 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 10¹¹ 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.