MiR-145 and miR-143 regulate smooth muscle cell fate and plasticity

Kimberly R. Cordes, Neil T. Sheehy, Mark P. White, Emily C. Berry, Sarah U. Morton, Alecia N. Muth, Ting Hein Lee, Joseph M. Miano, Kathryn N. Ivey, Deepak Srivastava

Research output: Contribution to journalArticle

1077 Scopus citations

Abstract

MicroRNAs (miRNAs) are regulators of myriad cellular events, but evidence for a single miRNA that can efficiently differentiate multipotent stem cells into a specific lineage or regulate direct reprogramming of cells into an alternative cell fate has been elusive. Here we show that miR-145 and miR-143 are co-transcribed in multipotent murine cardiac progenitors before becoming localized to smooth muscle cells, including neural crest stem-cell-derived vascular smooth muscle cells. miR-145 and miR-143 were direct transcriptional targets of serum response factor, myocardin and Nkx2-5 (NK2 transcription factor related, locus 5) and were downregulated in injured or atherosclerotic vessels containing proliferating, less differentiated smooth muscle cells. miR-145 was necessary for myocardin-induced reprogramming of adult fibroblasts into smooth muscle cells and sufficient to induce differentiation of multipotent neural crest stem cells into vascular smooth muscle. Furthermore, miR-145 and miR-143 cooperatively targeted a network of transcription factors, including Klf4 (Kruppel-like factor 4), myocardin and Elk-1 (ELK1, member of ETS oncogene family), to promote differentiation and repress proliferation of smooth muscle cells. These findings demonstrate that miR-145 can direct the smooth muscle fate and that miR-145 and miR-143 function to regulate the quiescent versus proliferative phenotype of smooth muscle cells.

Original languageEnglish (US)
Pages (from-to)705-710
Number of pages6
JournalNature
Volume460
Issue number7256
DOIs
StatePublished - Aug 6 2009

ASJC Scopus subject areas

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    Cordes, K. R., Sheehy, N. T., White, M. P., Berry, E. C., Morton, S. U., Muth, A. N., Lee, T. H., Miano, J. M., Ivey, K. N., & Srivastava, D. (2009). MiR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature, 460(7256), 705-710. https://doi.org/10.1038/nature08195