Development of direct cardiac reprogramming for clinical applications

The incidence of cardiovascular diseases is increasing worldwide, and cardiac regenerative therapy has great potential as a new treatment strategy, especially for ischemic heart disease. Direct cardiac reprogramming is a promising new cardiac regenerative therapy that uses defined factors to induce transdifferentiation of endogenous cardiac fibroblasts (CFs) into induced cardiomyocyte-like cells (iCMs). In vivo reprogramming is expected to restore lost cardiac function without necessitating cardiac transplantation by converting endogenous CFs that exist abundantly in cardiac tissues directly into iCMs. Indeed, we and other groups have demonstrated that in vivo cardiac reprogramming improves cardiac contractile function and reduces scar area after acute myocardial infarction (MI). Recently, we demonstrated that in vivo cardiac reprogramming is an innovative cardiac regenerative therapy that not only regenerates the myocardium, but also reverses fibrosis by inducing the quiescence of pro-fibrotic fibroblasts, thereby improving heart failure in chronic MI. In this review, we summarize the recent progresses in in vivo cardiac reprogramming, and discuss its prospects for future clinical applications and the challenges of direct human reprogramming, which has been a longstanding issue.