Molecular regulation mechanism of intestinal stem cells in mucosal injury and repair in ulcerative colitis

Ulcerative colitis (UC) is a recurrent intestinal inflammatory disease.Slit2, a secreted protein, interacts with its receptor Robo1 to regulate the differentiation of intestinal stem cells and participate in inflammation and tumor development.However, whether Slit2/Robo1involved in the pathogenesis of UC is not known.We investigated Slit2/Robo1-mediated UC using a dextran sodium sulfate (DSS)-induced model.Eight-week-old male Slit2-Tg (Slit2 transgene) mice, Robo1/2 +/- (Robo1 +/-Robo2 +/-) mice, and their WT littermates were allocated into two groups: (I) control group (n=10), of mice fed a normal diet and tap water and (II) DSS group (n=10), of mice fed a normal diet and drinking water with 2% DSS for 7 days.Colon tissues were collected and analyzed by qPCR, immunohistochemistry, western blot, and immunofluorescence.Slit2-Tg DSS mice showed less body weight loss, less blood in the stool, and less viscous stool compared to those of WT Slit DSS mice.Robo1/2 +/-DSS mice displayed a heavier degree of blood in the stool and a more apparent viscosity of the stool compared to those of WT Robo1/2 DSS mice.Slit2 overexpression maintained Lgr5 + stem cell proliferation in the crypt after DSS treatment, significantly increased the LC3II/I ratio, and slightly stimulated p62 expression in the crypt compared to those of DSS-induced WT Slit mice.Robo1/2 partial knockout reduced the number of Lgr5 + stem cells, decreased the LC3II/I ratio, and markedly increased p62 expression in the crypt compare to those of DSS-treated WT Robo1/2 mice.Our findings suggest that Slit2/Robo1 mediates DSS-induced UC probably by activating the autophagy of Lgr5 + stem cells.