PROJECT SUMMARY Heart disease is the number one killer in the Western world. Although heart transplant may be effective in treating heart failure, today’s most urgent problem in transplantation is the lack of suitable donor organs and tissues. Induced pluripotent stem cells (iPSCs) constitute a potential source of autologous patient-specific cardiomyocytes for cardiac repair, providing a major benefit over other sources of cells in terms of immune rejection. However, autologous transplantation has substantial challenges related to manufacturing and regulation. Although allogeneic transplantation is a promising alternative strategy, few immunological strategies have been proposed to overcome the immunological hurdle. We created a hypo-immunogenic mouse and a human hypo-iPSC line that both evade immune rejection, and we have successfully established their differentiation into mouse cardiomyocytes (mCMs) and human cardiac cells (hCCs). The proposed study is divided into three components to fully demonstrate the hypo-immunogenicity of our generated iPSCs. The first and second aims of this study is focused on studying the immune activation of the host receiving allogeneic mCMs/hypo-mCMs or allogeneic hCCs/hypo-hCCs, respectively, and on evaluation of the survival of implanted cells over time. State-of-the art immunological and imaging techniques will be utilized to demonstrate immune activation and cell survival. The third aim will investigate the ability of hypo-hCCs to increase remuscularization of the heart and to augment the functional performance of failing myocardium using a non-human primate model of myocardial ischemia-reperfusion and intra-myocardial delivery of hCCs over a three-month period. Successful completion of this study will provide insight into overcoming the immunobiological barrier in iPSC applications and the potential applicability of the hypo-hCCs in supporting functional recovery of failing myocardium.