Abstract

Background: Intramyocardial injection of human pluripotent stem cell-derived cardiomyocytes following a myocardial infarction (MI) improves cardiac function in large animal models, but associated ventricular arrhythmias are major safety concern. We hypothesized that transendocardial injection of human induced pluripotent stem cell (hiPSC)-derived committed cardiac progenitor cells (CCPs), combined with cardiac fibroblast-derived extracellular matrix (cECM) to enhance cell retention, will generate cardiac tissue grafts improving contractility without triggering ventricular arrhythmias. Methods: hiPSCs were differentiated using bioreactors and small molecules to produce committed cardiac progenitor cells (CCPs). MI was created using a coronary artery balloon occlusion and reperfusion model in Yucatan mini pigs. Four weeks later, epicardial needle injections of CCPs+cECM were performed in a small initial feasibility cohort (n=6), and then transendocardial injections of CCPs+cECM (n=14), CCPs alone (n=14), cECM alone (n=4) or vehicle control (n=13) into the peri-infarct region in a randomized cohort. Arrhythmias were evaluated using implanted event recorders. Magnetic resonance imaging (MRI) and invasive pressure-volume assessment were used to evaluate left ventricular anatomic and functional performance. Detailed histology was performed to detect and characterize human grafts. Results: A scalable biomanufacturing protocol was developed generating CCPs which can efficiently differentiate into cardiomyocytes or endothelial cells in vitro. Intramyocardial delivery of CCPs to post-MI porcine hearts resulted in engraftment and differentiation of CCPs to form ventricular cardiomyocyte rich grafts. There was no significant difference in cardiac MRI-based measured cardiac volumes or function between control, CCP and CCP+cECM groups; however, pressure-volume analysis showed an improvement in dobutamine-stimulated functional reserve in CCP and CCP+cECM groups. Delivery of CCPs did not result in tumors or ventricular arrhythmias. Conclusions: Transendocardial delivery of CCPs with or without cECM into post-MI porcine hearts resulted in comparable human cardiomyocyte grafts which did not improve resting LV function but did improve stress-induced contractile reserve without triggering ventricular arrhythmias.