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

Hiroyuki Yamakawa, Naoto Muraoka, Kazutaka Miyamoto, Taketaro Sadahiro, Mari Isomi, Sho Haginiwa, Hidenori Kojima, Tomohiko Umei, Mizuha Akiyama, Yuki Kuishi, Junko Kurokawa, Tetsushi Furukawa, Keiichi Fukuda, Masaki Ieda

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1128-1142
Number of pages15
JournalStem Cell Reports
Volume5
Issue number6
DOIs
Publication statusPublished - 2015 Dec 8

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Developmental Biology
  • Genetics

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  • Cite this

    Yamakawa, H., Muraoka, N., Miyamoto, K., Sadahiro, T., Isomi, M., Haginiwa, S., Kojima, H., Umei, T., Akiyama, M., Kuishi, Y., Kurokawa, J., Furukawa, T., Fukuda, K., & Ieda, M. (2015). Fibroblast Growth Factors and Vascular Endothelial Growth Factor Promote Cardiac Reprogramming under Defined Conditions. Stem Cell Reports, 5(6), 1128-1142. https://doi.org/10.1016/j.stemcr.2015.10.019