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

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  • Kimberly R. Cordes

    (Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA
    University of California, San Francisco, California 94543, USA
    University of California, San Francisco, California 94143, USA)

  • Neil T. Sheehy

    (Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA
    University of California, San Francisco, California 94543, USA
    University of California, San Francisco, California 94143, USA)

  • Mark P. White

    (Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA
    University of California, San Francisco, California 94543, USA
    University of California, San Francisco, California 94143, USA)

  • Emily C. Berry

    (Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA
    University of California, San Francisco, California 94543, USA
    University of California, San Francisco, California 94143, USA)

  • Sarah U. Morton

    (Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA
    University of California, San Francisco, California 94543, USA
    University of California, San Francisco, California 94143, USA)

  • Alecia N. Muth

    (Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA
    University of California, San Francisco, California 94543, USA
    University of California, San Francisco, California 94143, USA)

  • Ting-Hein Lee

    (Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA)

  • Joseph M. Miano

    (Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA)

  • Kathryn N. Ivey

    (Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA
    University of California, San Francisco, California 94543, USA
    University of California, San Francisco, California 94143, USA)

  • Deepak Srivastava

    (Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA
    University of California, San Francisco, California 94543, USA
    University of California, San Francisco, California 94143, USA)

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.

Suggested Citation

  • 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, 2009. "miR-145 and miR-143 regulate smooth muscle cell fate and plasticity," Nature, Nature, vol. 460(7256), pages 705-710, August.
    • Handle: RePEc:nat:nature:v:460:y:2009:i:7256:d:10.1038_nature08195
    DOI: 10.1038/nature08195
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    Cited by:

    1. Thomas R. W. Oliver & Lia Chappell & Rashesh Sanghvi & Lauren Deighton & Naser Ansari-Pour & Stefan C. Dentro & Matthew D. Young & Tim H. H. Coorens & Hyunchul Jung & Tim Butler & Matthew D. C. Nevill, 2022. "Clonal diversification and histogenesis of malignant germ cell tumours," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Hai Gao & Raviteja Reddy Guddeti & Yasushi Matsuzawa & Li-Ping Liu & Li-Xiao Su & Duo Guo & Shao-Ping Nie & Jie Du & Ming Zhang, 2015. "Plasma Levels of microRNA-145 Are Associated with Severity of Coronary Artery Disease," PLOS ONE, Public Library of Science, vol. 10(5), pages 1-13, May.

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