Human Induced Pluripotent Stem Cell‐Derived Committed Cardiac Progenitors Generate Cardiac Tissue Grafts in a Swine Ischemic Cardiomyopathy Model Without Triggering Ventricular Arrhythmias

BACKGROUND: Intramyocardial injection of human pluripotent stem cell-derived cardiomyocytes after myocardial infarction improves cardiac function in large animal models, but associated ventricular arrhythmias are a major safety concern. We hypothesized that transendocardial injection of human induced pluripotent stem cell-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: Human induced pluripotent stem cells were differentiated using a bioreactor and small molecules to produce CCPs. Myocardial infarction was created using a coronary artery balloon occlusion and reperfusion model in Yucatan mini pigs. Four weeks later, 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. Cardiac magnetic resonance imaging, invasive pressure-volume assessment, and immunohistology were performed. RESULTS: A scalable biomanufacturing protocol was developed generating CCPs. Intramyocardial delivery of CCPs to post-myocardial infarction porcine hearts resulted in engraftment and differentiation of CCPs, forming ventricular cardiomyocyte-rich grafts. There was no significant difference in cardiac magnetic resonance imaging-based measured cardiac volumes or function between control, CCP and CCP + cECM groups; however, pressure-volume analysis showed the greatest dobutamine-stimulated functional reserve in the CCP group. Delivery of CCPs did not result in tumors or ventricular arrhythmias. CONCLUSIONS: Transendocardial delivery of CCPs with or without cECM into postmyocardial infarction porcine hearts resulted in comparable human cardiomyocyte grafts that did not improve resting left ventricular function but CCPs did improve stress-induced contractile reserve without triggering ventricular arrhythmias.