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

Bing Zhao,Wei Fu,Chongkai Wang,Yehua Li,Ye-Guang Chen,Zhen Qi

doi:10.1038/ncomms8166

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.

Highlights

Lgr[5] þ stem cells are crucial to gut epithelium homeostasis, and therapies targeting these cells hold promise for treatment of gastrointestinal diseases
When exposed to 3% dextran sulphate sodium (DSS), only mild colonic epithelium injury was observed in Myh9fl/ þ ;Villin-cre mice, which was in contrast to severe colonic damage in Myh[9] þ / þ ;Villin-cre mice (Fig. 1d)
Colitis and other intestine degenerative diseases are common human disorders, but the clinical interventions are limited as the pathological mechanisms are not very clear

Summary

Introduction

Lgr[5] þ stem cells are crucial to gut epithelium homeostasis, and therapies targeting these cells hold promise for treatment of gastrointestinal diseases. Inhibition of NMII by blebbistatin or Myh[9] monoallelic deletion activates Akt through Rac[1] and PAK1, which is essential for the survival and pluripotency of Lgr[5] þ cells These results establish a critical role of the Myh9-Rac1PAK1-Akt pathway in the maintenance of Lgr[5] þ stem cells. Blebbistatin efficiently mitigates DSS-induced colitis and preserves Lgr[5] þ colonic stem cells in vivo These results reveal a novel signalling pathway that regulates Lgr[5] þ stem cell survival and pluripotency, and implicates a potential clinical application of blebbistatin to treat gastrointestinal epithelium injury and degeneration

Methods

Results

Conclusion