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Stem Cell Reports. 2017 Mar 14;8(3):548-560. doi: 10.1016/j.stemcr.2017.01.025. Epub 2017 Mar 2.

Notch Inhibition Enhances Cardiac Reprogramming by Increasing MEF2C Transcriptional Activity.

Author information

1
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA; Cell Plasticity and Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), c/Natzaret, 115-117, Barcelona 08035, Spain. Electronic address: mabad@vhio.net.
2
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
3
Department of Clinical Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
4
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. Electronic address: eric.olson@utsouthwestern.edu.

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.

KEYWORDS:

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

PMID:
28262548
PMCID:
PMC5355682
DOI:
10.1016/j.stemcr.2017.01.025
[Indexed for MEDLINE]
Free PMC Article

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