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EMBO J. 2014 Jul 17;33(14):1565-81. doi: 10.15252/embj.201387605. Epub 2014 Jun 11.

MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures.

Author information

1
Department of Clinical and Molecular Cardiovascular Research, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan Department of Cardiology, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan.
2
Department of Clinical and Molecular Cardiovascular Research, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan.
3
Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Bunkyo-ku Tokyo, Japan.
4
Department of Cardiology, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan.
5
Japan Biological Informatics Consortium (JBiC), Koto-ku Tokyo, Japan.
6
Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Koto-ku Tokyo, Japan.
7
Division of Cardiovascular Surgery, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan.
8
Department of Pediatrics, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan.
9
Department of Clinical and Molecular Cardiovascular Research, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan Department of Cardiology, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan JST CREST, Shinjuku-ku Tokyo, Japan mieda@z8.keio.jp.

Abstract

Fibroblasts can be directly reprogrammed into cardiomyocyte-like cells (iCMs) by overexpression of cardiac transcription factors or microRNAs. However, induction of functional cardiomyocytes is inefficient, and molecular mechanisms of direct reprogramming remain undefined. Here, we demonstrate that addition of miR-133a (miR-133) to Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Mesp1 and Myocd improved cardiac reprogramming from mouse or human fibroblasts by directly repressing Snai1, a master regulator of epithelial-to-mesenchymal transition. MiR-133 overexpression with GMT generated sevenfold more beating iCMs from mouse embryonic fibroblasts and shortened the duration to induce beating cells from 30 to 10 days, compared to GMT alone. Snai1 knockdown suppressed fibroblast genes, upregulated cardiac gene expression, and induced more contracting iCMs with GMT transduction, recapitulating the effects of miR-133 overexpression. In contrast, overexpression of Snai1 in GMT/miR-133-transduced cells maintained fibroblast signatures and inhibited generation of beating iCMs. MiR-133-mediated Snai1 repression was also critical for cardiac reprogramming in adult mouse and human cardiac fibroblasts. Thus, silencing fibroblast signatures, mediated by miR-133/Snai1, is a key molecular roadblock during cardiac reprogramming.

KEYWORDS:

Snai1; cardiomyocyte; microRNA; reprogramming; transcription factor

PMID:
24920580
PMCID:
PMC4198052
DOI:
10.15252/embj.201387605
[Indexed for MEDLINE]
Free PMC Article

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