The discovery of induced pluripotent stem cells (iPSCs) has revolutionized regenerative medicine. Autologous iPSCs can be generated by introducing 4 stem cell–specific factors (Oct4, Sox2, Klf4, c-Myc) into fibroblasts. iPSCs can propagate indefinitely and differentiate into clinically important cell types, including cardiomyocytes, in vitro. The iPSC-derived cardiomyocytes represent a promising source of cells for cell-based therapeutic approaches for cardiac regeneration. However, there are several challenges in the clinical application of iPSCs: tumorigenicity of immature cells, poor survival of the transplanted myocardial cells, and cost and efficacy of this therapeutic approach. We developed a new alternate approach for cardiac regeneration, called direct cardiac reprogramming. Instead of using stem cell factors, we overexpressed combinations of cardiac cell–specific genes in fibroblasts to directly induce cardiomyocytes without mediating through iPSCs. The direct reprogramming approach may overcome the challenges faced in the applicability of iPSC-based cell therapy. After the development of direct cardiac reprogramming, great progress has been made in improving the efficiency of direct cardiac reprogramming and applying this technology to regenerative medicine. Here, we provide an overview of the recent progress made, epigenetics, and potential clinical applications of direct cardiac reprogramming.
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