Direct reprogramming into cardiomyocytes

Abstract

Adult cardiomyocytes have little regenerative capacity following injury, and damaged myocardium heals via fibroblast proliferation and scar formation, leading to cardiac remodeling and heart failure. We and other reported that functional cardiomyocytes can be directly generated from fibroblasts using several combinations of cardiac-specific defined factors. Mouse fibroblasts can be directly converted into cardiomyocyte-like cells by overexpression of cardiac-specific transcription factors, Gata4, Mef2c, and Tbx5 (GMT), GMT plus Hand2 (GHMT), or Mef2c, Myocd, and Tbx5 in vitro. More recently, we and others reported that human fibroblasts can be reprogrammed into differentiated cardiomyocyte-like cells by overexpressing GMT plus Myocd and Mesp1 or Gata4, Hand2, Tbx5, Myocd, miR-1, and miR-133. We found that miR-133 promoted cardiac reprogramming by directly suppressing Snai1, a master gene of fibroblasts, and silencing fibroblast signature. In vivo cardiac reprogramming by GMT or GHMT also converted endogenous CFs into cardiomyocyte-like cells in situ, and improved cardiac function after acute myocardial infarction in mouse. These studies demonstrate that direct cardiac reprogramming technology may be a potential approach that could regenerate diseased hearts. The present article reviews the recent studies in cardiac reprogramming, and discusses the hopes and challenges of direct cardiac reprogramming towards regenerative therapy.