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 fibroblasts, which account for more than half of the cells in the heart, proliferate and synthesize extracellular matrix, leading to fibrosis and heart failure. As terminally differentiated cardiomyocytes 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 efficiency 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 fibroblasts mediating through stem cells. However, in 2010, we reported for the first time a novel method of the direct reprogramming of fibroblasts 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. Specifically, 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.