Abstract 12803: Human IPSC-Derived Committed Cardiac Progenitor Cells Engraft and Differentiate Following Transendocardial Injections in a Swine Ischemic Heart Failure Model

Abstract

Introduction: A hallmark of human myocardium is the inability to regenerate functional myocardium following myocardial infarction (MI) which can result in heart failure. In an effort to remuscularize infarcted myocardium, we tested a novel human iPSC-derived committed cardiac progenitor (CCP) cell population. Whether CCPs survive and differentiate to form grafts following transcatheter delivery in a clinically representative large animal model is unknown. Hypothesis: We hypothesized that transendocardial injection (TEI) of CCPs, combined with a cardiac fibroblast-derived matrix (CFM) particles as a cell retention agent leads to functional cardiac tissue grafts. Methods: Large MI following coronary artery balloon-occlusion reperfusion was induced in mini-swine that received a 4-drug immunosuppression regimen. 28 days later, TEI targeting the peri-infarct region was performed using combinations of 200 million CCPs with or without 50 mg CFM particles and Flexbumin control. 14 injections/pig were performed, and animals were followed for 4-8 weeks. Histopathology, continuous ECG recording and cardiac MRI were performed. Results: Human cell grafts were identified using Ku80+ human cell specific antibody in the initial n=11 evaluable CCP treated swine after 1 month (see representative image, Ku80+ human cells=green). The CCPs largely differentiate into TnI positive cardiomyocytes (red) in grafts observed at one month. Immunolabeling for a panel of cardiomyocyte markers confirmed the presence of human cardiomyocytes. Of n=29 initial pigs, no treatment-related safety issues were identified, such as post TEI pericardial effusion, ventricular tachyarrhythmias or tumors. Conclusions: TEI of CCPs, with and without CFM, resulted in grafts of human cardiomyocytes in the myocardium of immunosuppressed pigs, after 1 month post MI. Ongoing cardiac MRI analyses will determine the impact of CCP therapy on cardiac structure and function.