Transcription factor Tbx5 promotes cardiomyogenic differentiation of cardiac fibroblasts treated with 5-azacytidine.

Conversion of cardiac fibroblasts (CFs) into induced cardiomyocytes has recently been demonstrated, represents a potential therapeutic strategy for cardiac repair after myocardial injury. However, current approaches are inefficient. Here, we report that a defined transcription factor Tbx5, promoted cardiac reprogramming in the presence of a chemical inducer 5-azacytidine (5-aza). Morphological changes and cardiac specific genes and proteins expression were determined by immunofluorescence, quantitative real-time polymerase chain reaction, and Western blot analysis. Remarkably, Tbx5 enabled cardiac reprogramming with 5-aza by activating the expression of myocardial transcription-related genes, including cTnT, α-actin, Mef2c and inhibiting the expression of pluripotent genes such as Nanog, Oct4, and Sox2. Moreover, overexpression of Tbx5 upregulated the expression of sarcomere protein cTnT in CFs more efficiently at week 3 compared with 5aza-treated alone (P < 0.05). Conversely, inhibition of Tbx5 attenuated cardiac reprogramming. Furthermore, downregulated Tbx5 decreased wnt3a expression. At the same time, the inhibition effect of Tbx5i on cardiac reprogramming was reversed in vitro when these cells were exposed to Chir99021, a GSK-3 inhibitor. This finding provides new insight into the mechanism of cardiac reprogramming underlying the cardiac reprogramming process and lays the foundation for future clinical applications.

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