Key Regulators of Cardiovascular Differentiation and Regeneration: Harnessing the Potential of Direct Reprogramming to Treat Heart Failure

Cardiovascular diseases remain a leading cause of death worldwide, with the number of patients with heart failure increasing rapidly in aging societies. As adult cardiomyocytes are terminally differentiated cells and opportunities for heart transplantation are very limited, regenerative medicine may become a game changer in heart failure treatment. To develop strategies for generating cardiomyocytes, vascular cells, and other supporting cells, it is necessary to understand the mechanism of cardiovascular differentiation during development and from pluripotent stem cells. Master regulators for cardiovascular differentiation can generate new cardiomyocytes and vascular cells directly from other differentiated cells such as fibroblasts. Fibroblasts can be directly reprogrammed into cardiomyocytes by overexpressing a combination of 3 cardiac-specific transcription factors (Gata4, Mef2c, Tbx5) both in vitro and in vivo, which restores cardiac function after myocardial infarction in mice. Moreover, a direct reprogramming-based approach can be used to identify new key regulators of the cardiovascular mesoderm, which can differentiate into all 3 types of cardiovascular cells including cardiomyocytes, endothelial cells, and smooth muscle cells. This review provides a perspective on how key regulators for cardiovascular differentiation and regeneration can be identified and used to develop new treatments for heart failure.