Direct cardiac reprogramming: A novel approach for heart regeneration

Cardiac diseases are among the most common causes of death globally. Cardiac muscle has limited proliferative capacity, and regenerative therapies are highly in demand as a new treatment strategy. Although pluripotent reprogramming has been developed, it has obstacles, such as a potential risk of tumor formation, poor survival of the transplanted cells, and high cost. We previously reported that fibroblasts can be directly reprogrammed to cardiomyocytes by overexpressing a combination of three cardiac-specific transcription factors (Gata4, Mef2c, Tbx5 (together, GMT)). We and other groups have promoted cardiac reprogramming by the addition of certain miRNAs, cytokines, and epigenetic factors, and unraveled new molecular mechanisms of cardiac reprogramming. More recently, we discovered that Sendai virus (SeV) vector expressing GMT could efficiently and rapidly reprogram fibroblasts into integration-free cardiomyocytes in vitro via robust transgene expression. Gene delivery of SeV-GMT also improves cardiac function and reduces fibrosis after myocardial infarction in mice. Through direct cardiac reprogramming, new cardiomyocytes can be generated and scar tissue reduced to restore cardiac function, and, thus, direct cardiac reprogramming may serve as a powerful strategy for cardiac regeneration. Here, we provide an overview of the previous reports and current challenges in this field.