Improve Electrical Integration of hiPSC-derived cardiac tissue with Host Heart

About This Grant

Project Summary Adult human hearts cannot regenerate cardiomyocytes (CMs) to repair the damaged myocardium following injury. Instead, the injured heart undergoes extensive remodeling which may eventually lead to heart failure. Implantation of CMs derived from stem cells into the damaged myocardium has shown promising therapeutic results. One strategy is implanting the human induced pluripotent stem cell (hiPSC) derived cardiac tissue to repair the myocardium. The implanted tissue engrafts with the host heart and reconstructs the damaged muscular tissue. Electrical integration between the implanted graft tissue and the host heart is an important consideration. Proper electrical integration ensures that implanted graft can contract in synchrony with host heart and will not become a source of arrhythmia. A prerequisite for investigating the electrical interaction between the graft and host myocardium is that a substantial number of implanted CMs must survive for a sufficient period in the heart of a clinically relevant large animal model. Additionally, there must be a technical platform to detect the electrical activity of implanted CMs located deep inside the host myocardium. Recently, all these technical prerequisites have been resolved in our laboratory. In our prior study, we found that the implanted hiPSC-CM spheroids can survive in a porcine myocardial infarction model for at least 7 days. With our newly developed technical platform, our prior study highlights two major challenges in host-graft electrical integration: 1, electrical coupling along the host-graft interface is spatially sparse; 2, the in-graft electrical conduction is slow. Poor electrical integration not only impedes functional remuscularization, but also highlights a long-standing concern regarding the pro-arrhythmic effect associated with cardiac cell therapy. In this project, our first goal is to investigate the effects of connexin-43 (Cx43) over-expression to the host-graft electrical coupling. We expect that Cx43 over-expression will promote electrical coupling along the host-graft interface. Our second goal is to improve the compatibility of electrical conduction between the host and graft. We expect that the hiPSC graft with enhanced electrical conduction will be less arrhythmogenic than its wild-type counterpart. To our knowledge, this is the first attempt to directly intervene in the process of electrical integration between engineered cardiac tissue and the host heart in a large animal model. The results of the proposed project will guide a critical translational step toward the future clinical application of cardiac cell therapy.