Notch Inhibition Enhances Cardiac Reprogramming by Increasing MEF2C Transcriptional Activity

Maria Abad, Hisayuki Hashimoto, Huanyu Zhou, Maria Gabriela Morales, Beibei Chen, Rhonda Bassel-Duby, Eric N. Olson

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Conversion of fibroblasts into functional cardiomyocytes represents a potential means of restoring cardiac function after myocardial infarction, but so far this process remains inefficient and little is known about its molecular mechanisms. Here we show that DAPT, a classical Notch inhibitor, enhances the conversion of mouse fibroblasts into induced cardiac-like myocytes by the transcription factors GATA4, HAND2, MEF2C, and TBX5. DAPT cooperates with AKT kinase to further augment this process, resulting in up to 70% conversion efficiency. Moreover, DAPT promotes the acquisition of specific cardiomyocyte features, substantially increasing calcium flux, sarcomere structure, and the number of spontaneously beating cells. Transcriptome analysis shows that DAPT induces genetic programs related to muscle development, differentiation, and excitation-contraction coupling. Mechanistically, DAPT increases binding of the transcription factor MEF2C to the promoter regions of cardiac structural genes. These findings provide mechanistic insights into the reprogramming process and may have important implications for cardiac regeneration therapies.

Original languageEnglish (US)
Pages (from-to)548-560
Number of pages13
JournalStem Cell Reports
Volume8
Issue number3
DOIs
StatePublished - Mar 14 2017

Keywords

  • cardiomyocytes
  • cell-fate conversion
  • DAPT
  • direct cellular reprogramming
  • heart regeneration
  • Notch signaling
  • regenerative medicine
  • transdifferentiation

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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