Direct Cardiac Reprogramming for Regenerative Medicine

Abstract

Despite recent progress in cardiovascular biology and medicine, heart failure remains a leading cause of death and new therapies are highly demanded. Due to the limited regenerative capacity of cardiomyocytes, regenerative therapy has emerged as an attractive approach for the treatment of heart failure, and direct cardiac reprogramming from fibroblasts might be a powerful strategy toward this goal. We first reported that a combination of three cardiac-specific transcription factors, Gata4, Mef2c, and Tbx5 (GMT), could directly reprogram mouse fibroblasts into cardiomyocytelike cells in vitro (Ieda et al. Cell, 2010). Subsequently, we and others demonstrated that gene transfer of the cardiac reprogramming factors in the mouse infarct hearts could directly convert endogenous cardiac fibroblasts into cardiomyocyte-like cells in vivo (Inagawa et al. Circ Res, 2012). In human, addition of Myocd and Mesp1 to GMT (GMTMM) reprogrammed human cardiac fibroblasts into cardiomyocyte-like cells (Wada et al. PNAS, 2013). More recently, we found that addition of muscle-specific miRNA, miR-133, to GMTMM enhanced cardiac reprogramming in human fibroblasts by 10-fold. Mechanistically, mir-133 promoted cardiac reprogramming by targeting Snai1, a master gene of fibroblasts, and silencing fibroblast signatures (Muraoka et al. EMBO J, 2014). Although more refinements are needed, these findings might inform new regenerative strategies for the treatment of heart failure.