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

Naoto Muraoka, Hiroyuki Yamakawa, Kazutaka Miyamoto, Taketaro Sadahiro, Tomohiko Umei, Mari Isomi, Hanae Nakashima, Mizuha Akiyama, Rie Wada, Kohei Inagawa, Takahiko Nishiyama, Ruri Kaneda, Toru Fukuda, Shu Takeda, Shugo Tohyama, Hisayuki Hashimoto, Yoshifumi Kawamura, Naoki Goshima, Ryo Aeba, Hiroyuki YamagishiKeiichi Fukuda, Masaki Ieda

Research output: Contribution to journalArticle

154 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1565-1581
Number of pages17
JournalEMBO Journal
Volume33
Issue number14
DOIs
Publication statusPublished - 2014 Jul 17

Keywords

  • Snai1
  • cardiomyocyte
  • microRNA
  • reprogramming
  • transcription factor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Muraoka, N., Yamakawa, H., Miyamoto, K., Sadahiro, T., Umei, T., Isomi, M., Nakashima, H., Akiyama, M., Wada, R., Inagawa, K., Nishiyama, T., Kaneda, R., Fukuda, T., Takeda, S., Tohyama, S., Hashimoto, H., Kawamura, Y., Goshima, N., Aeba, R., ... Ieda, M. (2014). MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures. EMBO Journal, 33(14), 1565-1581. https://doi.org/10.15252/embj.201387605