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MiR‐133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures
Author(s) -
Muraoka Naoto,
Yamakawa Hiroyuki,
Miyamoto Kazutaka,
Sadahiro Taketaro,
Umei Tomohiko,
Isomi Mari,
Nakashima Hanae,
Akiyama Mizuha,
Wada Rie,
Inagawa Kohei,
Nishiyama Takahiko,
Kaneda Ruri,
Fukuda Toru,
Takeda Shu,
Tohyama Shugo,
Hashimoto Hisayuki,
Kawamura Yoshifumi,
Goshima Naoki,
Aeba Ryo,
Yamagishi Hiroyuki,
Fukuda Keiichi,
Ieda Masaki
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201387605
Subject(s) - snai1 , reprogramming , mef2c , biology , gene knockdown , microbiology and biotechnology , fibroblast , gene silencing , gata4 , cardiac fibrosis , microrna , embryonic stem cell , transcription factor , downregulation and upregulation , epithelial–mesenchymal transition , gene , fibrosis , cell culture , genetics , medicine
Abstract Fibroblasts can be directly reprogrammed into cardiomyocyte‐like cells ( iCM s) 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 iCM s 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 iCM s 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 iCM s. 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.