Direct cardiac reprogramming: Progress and challenges in basic biology and clinical applications

The discovery of induced pluripotent stem cells changed the field of regenerative medicine and inspired the technological development of direct reprogramming or the process by which one cell type is directly converted into another without reverting a stem cell state by overexpressing lineage-specific factors. Indeed, direct reprogramming has proven sufficient in yielding a diverse range of cell types from fibroblasts, including neurons, cardiomyocytes, endothelial cells, hematopoietic stem/progenitor cells, and hepatocytes. These studies revealed that somatic cells are more plastic than anticipated, and that transcription factors, microRNAs, epigenetic factors, secreted molecules, as well as the cellular microenvironment are all important for cell fate specification. With respect to the field of cardiology, the cardiac reprogramming presents as a novel method to regenerate damaged myocardium by directly converting endogenous cardiac fibroblasts into induced cardiomyocyte-like cells in situ. The first in vivo cardiac reprogramming reports were promising to repair infarcted hearts; however, the low induction efficiency of fully reprogrammed, functional induced cardiomyocyte-like cells has become a major challenge and hampered our understanding of the reprogramming process. Nevertheless, recent studies have identified several critical factors that may affect the efficiency and quality of cardiac induction and have provided new insights into the mechanisms of cardiac reprogramming. Here, we review the progress in direct reprogramming research and discuss the perspectives and challenges of this nascent technology in basic biology and clinical applications.