Pluripotent stem cell-based approaches for heart repair and the potential of genetic modifications.

The limited regenerative capacity of the heart contributes to the pathology of heart failure, a growing global challenge in aging societies, particularly in the absence of effective treatments for advanced stages of the disease. With heart transplants constrained by donor shortages, alternative therapies are needed. Cellular therapies, particularly using induced pluripotent stem cells (iPSCs), show promise in producing functional cardiomyocytes and other cardiac cell types, driving preclinical and clinical studies. This review addresses the challenges inherent in using pluripotent stem cell-based approaches for heart repair. Key issues include developing efficient methods for the large-scale production of mature cardiomyocytes, particularly those with properties that minimize the risk of engraftment arrhythmias, and enhancing the proliferation and engraftment efficacy of transplanted cells while mitigating the risk of overproliferation. The review highlights how genetic modifications of pluripotent stem cell-derived cardiomyocytes can improve transplantation outcomes. Additionally, it examines the potential of pluripotent stem cell-derived progenitors and the co-delivery of cardiomyocytes with endothelial cells to overcome inadequate engraftment, vascularization, and arrhythmias observed when cardiomyocytes are delivered alone.