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The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells

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  • Bing Zhao

    (The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Zhen Qi

    (The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Yehua Li

    (The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Chongkai Wang

    (Peking University Third Hospital)

  • Wei Fu

    (Peking University Third Hospital)

  • Ye-Guang Chen

    (The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

Abstract

Lgr5+ stem cells are crucial to gut epithelium homeostasis, and therapies targeting these cells hold promise for treatment of gastrointestinal diseases. Here we report that the non-muscle-myosin-II (NMII) heavy chain Myh9 accumulates at epithelial injury sites in mice distal colon treated with dextran sulphate sodium (DSS). Gut-epithelium-specific Myh9 monoallelic deletion alleviates DSS-induced colonic crypt damage and acute colitis. Consistently, the NMII inhibitor blebbistatin can improve the survival of Lgr5+ stem cells and the growth of Lgr5 organoids. Mechanistically, inhibition of NMII by blebbistatin or Myh9 monoallelic deletion activates Akt through Rac1 and PAK1, which is essential for the survival and pluripotency of Lgr5+ cells. These results establish a critical role of the Myh9-Rac1-PAK1-Akt pathway in the maintenance of Lgr5+ stem cells. As blebbistatin can mitigate DSS-induced colitis and preserve Lgr5+ colonic stem cells in vivo, our findings provide a potential therapeutic intervention of gastrointestinal epithelium injury and degenerative diseases.

Suggested Citation

  • Bing Zhao & Zhen Qi & Yehua Li & Chongkai Wang & Wei Fu & Ye-Guang Chen, 2015. "The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8166
    DOI: 10.1038/ncomms8166
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    Cited by:

    1. Liang Yang & Zifeng Ruan & Xiaobing Lin & Hao Wang & Yanmin Xin & Haite Tang & Zhijuan Hu & Yunhao Zhou & Yi Wu & Junwei Wang & Dajiang Qin & Gang Lu & Kerry M. Loomes & Wai-Yee Chan & Xingguo Liu, 2024. "NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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