TY - JOUR
T1 - Notch Inhibition Enhances Cardiac Reprogramming by Increasing MEF2C Transcriptional Activity
AU - Abad, Maria
AU - Hashimoto, Hisayuki
AU - Zhou, Huanyu
AU - Morales, Maria Gabriela
AU - Chen, Beibei
AU - Bassel-Duby, Rhonda
AU - Olson, Eric N.
N1 - Publisher Copyright:
© 2017 The Authors
PY - 2017/3/14
Y1 - 2017/3/14
N2 - 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.
AB - 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.
KW - DAPT
KW - Notch signaling
KW - cardiomyocytes
KW - cell-fate conversion
KW - direct cellular reprogramming
KW - heart regeneration
KW - regenerative medicine
KW - transdifferentiation
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U2 - 10.1016/j.stemcr.2017.01.025
DO - 10.1016/j.stemcr.2017.01.025
M3 - Article
C2 - 28262548
AN - SCOPUS:85014097486
SN - 2213-6711
VL - 8
SP - 548
EP - 560
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 3
ER -