The Role Of BMP Signaling In Regulating The Self-renewal Of Lgr5~+ Intestinal Stem Cell

The adult stem cells in intestine can continually self-renew,proliferate and differentiate to fuel the renewal of intestinal epithelium.In mammals,the intestinal epithelium is structurally divided into protrusion like villus and invagination like crypts.The Lgr5~+intestinal stem cells reside at the base of crypts and keep tight contact with Paneth cells.The actively proliferating Lgr5~+stem cells undergo fast self-renewal and divide every 24 hours.The self-renewal ability of Lgr5~+stem cells is under tight control by important signals in the stem cell niche and the dysfunction of these signals may lead to intestinal disorders including colitis and colorectal cancer.BMP represents an important niche signal.It was reported that BMP plays an important role in balancing the Wnt-driven proliferation of intestinal epithelium.However,the mechanism underlying the negative effects of BMP on intestinal epithelium is unclear,which largely limites the therapeutic targeting of this pathway.In the present study,we studied the role of BMP signaling in regulating the self-renewal of Lgr5~+intestinal stem cells under both injury condition and homeostatic condition.Firstly,we found the BMP-Myh9 cascade mediates the epithelium injury through impairing the self-renewal of Lgr5~+stem cells in the Dextran sulfate sodium(DSS)induced colitis model.Then,we investigated the function of BMP signaling during the normal intestinal homestasis using the inducible intestinal specific BMP receptor knockout mouse model.We found that loss of BMP signaling leads to rapid expansion of Lgr5~+stem cells and promotes the formation of intestinal polyps fueled by hyperactive Lgr5~+stem cells.BMP functions through direct transcriptional repression of a large number of intestinal stem cell signature genes but not through inhibition of Wnt signaling.Smad proteins mediate this process through binding to the gene promoters and recruiting histone deacetylase HDAC1.In conclusion,our study unraveal the mechanisms underlying the BMP function in regulating Lgr5~+intestinal stem cells under both injury condition and homeostatic condition.Our findings are important for the understanding of stem cell maintenance and for therapeutic treatment of intestinal diseases.