Human pluripotent stem cell-based cardiac repair: Lessons learned and challenges ahead.

The transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and hPSC-derived cardiac progenitors (hPSC-CPs) represents a promising strategy for regenerating hearts damaged by myocardial infarction (MI). After nearly two decades of experience testing these cell populations in various small- and large-animal MI models, multiple clinical trials have recently been initiated. In this review, we consider the principal lessons learned from preclinical experience with hPSC-CMs and -CPs, focusing on three conclusions that have been supported by the majority of reported transplantation studies. First, hPSC-CMs and -CPs stably engraft in injured hearts and partially remuscularize the infarct scar, but more progress is needed to improve graft cell retention and survival. Second, the transplantation of hPSC-CMs and -CPs has been found to improve contractile function in infarcted hearts, but the mechanistic basis for these effects remains incompletely elucidated. Third, the graft tissue formed by these cells can integrate and activate synchronously with host myocardium, but this capacity for electromechanical integration has been associated with an elevated risk of graft-related arrhythmias. Here, we summarize the preclinical evidence supporting these three observations, identify the relevant gaps and barriers to translation, and summarize ongoing efforts to improve the safety and efficacy of hPSC-CM- and -CP-based regenerative therapies.