Abstract P1079: Regeneration Of Primate Hearts With Human IPS Cell-derived Cardiac Spheroids

Abstract

Background: Clinical application of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for cardiac repair started with the epicardial delivery of engineered cardiac tissue; however, the feasibility of the direct delivery of hiPSC-CMs into the cardiac muscle layer, which was shown to induce electrical integration, was unclear because of concerns regarding poor engraftment of dispersed cardiomyocytes (CMs) and post-transplant arrhythmias. Thus, in this study, we prepared clinical-grade purified hiPSC-CM aggregates, known as cardiac spheroids (CSs), and confirmed whether the direct injection of CSs could regenerate infarcted non-human primate hearts. Methods: We performed two separate experiments to explore the appropriate number of CMs derived from human induced pluripotent stem cells (hiPSCs). In the first experiment, 10 cynomolgus monkeys were subjected to myocardial infarction 2 weeks pre-transplantation and were designated as recipients of CSs containing 2х10 7 CMs or the vehicle. The animals were killed 12 weeks post-transplantation for histological analysis, and cardiac function and arrhythmia were monitored during the observational period. In the second study, we repeated the equivalent transplantation study using more CMs (6х10 7 CMs). Results: Recipients of CSs containing 2х10 7 CMs showed limited CM grafts and transient increases in fractional shortening compared with those of the vehicle, with a low incidence of post-transplant arrhythmia. Transplantation of increased dose of CMs resulted in significantly greater engraftment and long-term contractile benefits. The incidence of post-transplant arrhythmia slightly increased in recipients of CSs containing 6х10 7 CMs. Conclusions: We demonstrated that direct injection of hiPSC-derived CSs, prepared as clinical-grade cell products, restores the contractile functions of injured primate hearts with an acceptable risk of post-transplant arrhythmia. These findings provide strong rationale for conducting clinical trials using the equivalent CM products.