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Stem Cell Reports. 2015 Dec 8;5(6):1128-1142. doi: 10.1016/j.stemcr.2015.10.019. Epub 2015 Nov 25.

Fibroblast Growth Factors and Vascular Endothelial Growth Factor Promote Cardiac Reprogramming under Defined Conditions.

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Department of Cardiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Department of Bio-Informational Pharmacology, Medical Research Institute, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Department of Cardiology, Keio University School of Medicine, Tokyo 160-8582, Japan; JST, CREST, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address:


Fibroblasts can be directly reprogrammed into cardiomyocyte-like cells (iCMs) by overexpression of cardiac transcription factors, including Gata4, Mef2c, and Tbx5; however, this process is inefficient under serum-based culture conditions, in which conversion of partially reprogrammed cells into fully reprogrammed functional iCMs has been a major hurdle. Here, we report that a combination of fibroblast growth factor (FGF) 2, FGF10, and vascular endothelial growth factor (VEGF), termed FFV, promoted cardiac reprogramming under defined serum-free conditions, increasing spontaneously beating iCMs by 100-fold compared with those under conventional serum-based conditions. Mechanistically, FFV activated multiple cardiac transcriptional regulators and converted partially reprogrammed cells into functional iCMs through the p38 mitogen-activated protein kinase and phosphoinositol 3-kinase/AKT pathways. Moreover, FFV enabled cardiac reprogramming with only Mef2c and Tbx5 through the induction of cardiac reprogramming factors, including Gata4. Thus, defined culture conditions promoted the quality of cardiac reprogramming, and this finding provides new insight into the mechanism of cardiac reprogramming.

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