జర్నల్ ఆఫ్ స్టెమ్ సెల్ రీసెర్చ్ & థెరపీ

నైరూప్య

In vivo Direct Reprogramming of Fibroblasts into Cardiomyocyte-Like Cells Though Inhibition of HDACs and TGF-β Pathway

Hua Li, Junbo Ge and Gang Pei

Background: Substantial progress has been recently achieved that direct lineage reprogramming induced by small molecule compounds was possible either in vitro or in vivo, which provided a promising cellular strategy for regenerative therapy. Method: A combination of an inhibitor of HDACs, valproic acid (V) and an inhibitor of TGF-β pathway, tranilast (T) were applied to identify the conversation of fibroblasts into induced cardiomyocyte-like cells (iCMs) in situ in mice with myocardial infarction. Result: We found that the combination of two small molecules, V&T could reprogram cardiac fibroblasts into iCMs in vivo, which were co-labeled with vimentin and a-actin 4 weeks after myocardial infarction; while, the phenomenon was found neither in mice with non-myocardial infarction nor in mice with myocardial infarction induced only by physiological saline. And furthermore, these iCMs resembled mouse native cardiomyocytes regarding their specific molecular phenotypes: a-MHC, c-TnT, connexin-43. However, the early marker of progenitor cells prior to cardiac differentiation, Mesp1, wasn’t detected in the infarcted and border zone. Conclusion: HDACs and TGF-β inhibitors jointly could achieve direct cardiac reprogramming from cardiac fibroblasts in vivo, without establishing a pluripotent state and thus, provide a new important therapeutic application for cardiac regeneration.