In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes

The reprogramming of adult cells into pluripotent cells or directly into alternative adult cell types holds great promise for regenerative medicine. We reported previously that cardiac fibroblasts, which represent 50% of the cells in the mammalian heart, can be directly reprogrammed to adult cardiomyocyte-like cells in vitro by the addition of Gata4, Mef2c and Tbx5 (GMT). Here we use genetic lineage tracing to show that resident non-myocytes in the murine heart can be reprogrammed into cardiomyocyte-like cells in vivo by local delivery of GMT after coronary ligation. Induced cardiomyocytes became binucleate, assembled sarcomeres and had cardiomyocyte-like gene expression. Analysis of single cells revealed ventricular cardiomyocyte-like action potentials, beating upon electrical stimulation, and evidence of electrical coupling. In vivo delivery of GMT decreased infarct size and modestly attenuated cardiac dysfunction up to 3 months after coronary ligation. Delivery of the pro-angiogenic and fibroblast-activating peptide, thymosin β4, along with GMT, resulted in further improvements in scar area and cardiac function. These findings demonstrate that cardiac fibroblasts can be reprogrammed into cardiomyocyte-like cells in their native environment for potential regenerative purposes. Previous work has shown that a combination of three transcription factors can directly reprogram cardiac fibroblasts into cardiomyocyte-like cell in vitro ; now, the same authors demonstrate in vivo reprogramming of cardiac fibroblasts into induced cardiomyocytes. Heart-tissue regeneration in mice Having shown previously that a combination of three transcription factors can directly reprogram cardiac fibroblasts to cardiomyocyte-like cells — the cells that drive the heartbeat — in vitro , Deepak Srivastava and colleagues now take this approach in vivo . Using a retrovirus to deliver the transcription factors directly to the hearts of adult mice, they demonstrate the conversion of non-myocytes to induced cardiomyocytes. Heart function improved and the area of damaged tissue shrank. Delivery of the multifunctional peptide thymosin β4 — which activates cardiac fibroblasts — along with the cardiac reprogramming factors resulted in further reduction in scar area and improvement in cardiac function.