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

Nature. 2009 Aug 6;460(7256):705-10. doi: 10.1038/nature08195. Epub 2009 Jul 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Lineage*
  • Cell Proliferation
  • Female
  • Gene Expression Regulation
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Models, Biological
  • Myocardium / metabolism
  • Myocytes, Smooth Muscle / cytology*
  • Myocytes, Smooth Muscle / metabolism*
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Vascular Diseases / metabolism
  • ets-Domain Protein Elk-4 / metabolism

Substances

  • Elk4 protein, mouse
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins
  • MIRN145 microRNA, mouse
  • MicroRNAs
  • Mirn143 microRNA, mouse
  • Nkx2-5 protein, mouse
  • Transcription Factors
  • ets-Domain Protein Elk-4