Proceedings of the Uehara Memorial Foundation. Innovative Medicine: Basic Research and Development. Cardiac Reprogramming for Heart Repair

Heart disease remains the leading cause of death worldwide. Terminally differentiated cardiomyocytes do not possess regenerative capacity, and heart disease is irreversible. Stem cell–derived cardiomyocytes are an attractive cell source for heart regeneration, but the risk of tumor formation due to contamination of stem cells, the complicated process of cell transplantation, and poor survival of the transplanted cells may be challenges for this approach. The discovery of reprogramming of fibroblasts into induced pluripotent stem cells (iPSCs) by the Yamanaka factors, Oct4, Sox2, Klf4, and c-Myc, inspired a new strategy to generate desired cell types from fibroblasts. It has been demonstrated that a diverse range of cell types, such as pancreatic β cells, blood cells, neurons, chondrocytes, and hepatocytes, can be directly generated from fibroblasts, using lineage-specific transcription factors. We first reported that functional cardiomyocytes can be generated from mouse fibroblasts using cardiac-specific transcription factors, Gata4, Mef2c, and Tbx5 (GMT) in vitro. Our subsequent work revealed that GMT can also convert resident cardiac fibroblasts into cardiomyocyte-like cells in infarcted mouse hearts. We also demonstrated that Gata4, Mef2c, Tbx5, Myocd, and Mesp1 (GMTMM) can convert human fibroblasts into cardiomyocyte-like cells, and that addition of miR-133 to GMT or GMTMM promoted cardiac reprogramming in mouse and human fibroblasts. Intriguingly, miR-133 directly suppressed Snai1, a master gene of epithelial-to-mesenchymal transition, which in turn repressed fibroblast signatures and promoted cardiac reprogramming. Here, I review the recent studies in cardiac reprogramming and discuss the perspectives and challenges of this innovative technology toward regenerative therapy.