Direct cardiac reprogramming by epigenetic factors and micro RNAs

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Direct reprogramming of fibroblasts into cells of interest holds great promise for regenerative medicine. Generation of cardiomyocyte-like cells from mouse fibroblasts was achieved by transduction of Gata4, Mef2c, and Tbx5 (GMT). However, the induction of fully reprogrammed functional cardiomyocytes is inefficient and the reprogramming mechanisms remain undefined. Here we demonstrate that cardiac microRNA promotes direct cardiac reprogramming from mouse embryonic fibroblasts (MEFs) and postnatal tail-tip fibroblasts. MiRNA overexpression with GMT transduction increased the generation rate of beating cardiomyocyte-like cells from MEFs by 7-fold compared to GMT alone, and shortened the duration to induce beating cells to 10 days. Molecularly, we found that fibroblast genes were suppressed early in reprogramming by miRNA overexpression. Thus, miRNA promotes direct cardiac reprogramming partly through silencing fibroblast signatures.