Strategies for heart regeneration approaches ranging from induced pluripotent stem cells to direct cardiac reprogramming

Cardiovascular disease remains a leading cause of death for which current therapeutic regimens are limited. Following myocardial injury, endogenous cardiac fbroblasts, which account for more than half of the cells in the heart, proliferate and synthesize extracellular matrix, leading to fbrosis and heart failure. As terminally differentiated cardiomyo-cytes have little regenerative capacity following injury, development of cardiac regenerative therapy is highly desired. Embryonic stem (ES) and induced pluripotent stem (iPS) cells are promising tools for regenerative medicine; however, these stem cells demonstrate variable cardiac differentiation effciency and tumorigenicity, which should be solved for clinical applications. Up until the last decade, it was an established theory that cardiomyocytes could only be produced from fbroblasts mediating through stem cells. However, in 2010, we reported for the frst time a novel method of the direct reprogramming of fbroblasts into cardiomyocytes, demonstrating various reprogramming pathways exist. This review summarizes the latest trends in stem cell and regenerative research, touching upon iPS cells, partial reprogramming strategy, and direct cardiac reprogramming. Specifcally, we examine the many recent advances in both in vitro and in vivo direct cardiac reprogramming, and explore the application of these methods to cardiovascular regenerative medicine.