Abstract 13963: Evidence of Content-Dependent Functional and Electrical Coupling of Human Induced Pluripotent Stem Cell-Derived Engineered Cardiac Tissue With Chronic Infarct Rat Myocardium

Abstract

Background: It has been shown that transplantation of engineered cardiac tissue (ECT) derived from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) into the infarct heart induces electrical communication between the ECT and the native myocardium; however, factors enhancing the electrical integrity and thus the therapeutic effects are not fully understood. We herein hypothesized that content of cardiomyocytes in the ECT may be a key to achieve efficient electrical coupling and functional contribution in chronic rat myocardial infarction (MI) heart. Methods and Results: Neonatal rat cardiomyocytes (NRCM), mimicking the host myocardium, were partially covered by the ECT containing iPSC-CMs produced by thermoresponsive culture dishes in vitro , to explore electrical communication of the ECT with myocardium. As a result, the NRCM and the ECT showed spontaneous, individual contractions for 2 hours, though they gradually showed electrical and motional synchronization, featuring transmitted electrical pulse from the NRCM to the ECT, as assessed by multi-electrode array. Subsequently, the ECT of different ratios (25, 50, 70, and 90%) of iPSC-CMs were generated by magnetic-activated cell sorting using cardiac specific cell surface marker. As a result, the 70% group exhibited the highest contractile and relaxation properties in vitro , as assessed by high-speed video microscopy image-based motion analysis and Ca transient measurement. Finally, the ECTs including 25, 50, 70% CMs were transplanted to immune deficient rat MI model (n=7 each). As a result, ejection fraction was significantly improved in the 50% (52±10%) and 70% (52±12%) groups, but not in the 25% group (35±5%), as compared to the control (35±10%; P <0.05). Epicardial optical mapping of Langendorff perfused heart on day 3 showed that the ECTs of 50% and the 70% groups exhibited electrical activity and synchronization with the native myocardium. Conclusion: Transplantation of the ECT improved cardiac performance associated with synchronization with the myocardium in rat infarction model, dependent upon content of the cardiomyocytes in the ECT. It was thus suggested that transplanted ECT may behave “working cardiac construct” in the damaged heart.