Cooperation of Wnt/β-catenin and Dll1-mediated Notch pathway in Lgr5-positive intestinal stem cells regulates the mucosal injury and repair in DSS-induced colitis mice model  

作　　者：Weijun Ou Weimin Xu Yaosheng Wang Zhebin Hua Wenjun Ding Long Cui Peng Du 

机构地区：[1]Department of Colorectal Surgery,Xinhua Hospital,Shanghai Jiaotong University,School of Medicine,Shanghai,P.R.China [2]Shanghai Colorectal Cancer Research Center,Shanghai,P.R.China

出　　处：《Gastroenterology Report》2024年第1期424-434,共11页胃肠病学报道(英文)

基　　金：supported by the National Natural Science Foundation of China[No.82000481,81570474,and 82270549].

摘　　要：Background:Lgr5-positive cells located in the basal layer of crypts have self-regenerative and proliferative differentiation potentials of intestinal stem cells(ISCs),maintaining a balance of regeneration-repair in mucosal epithelium.However,the mechanisms of mucosal repair that are regulated by ISCs in ulcerative colitis(UC)remain unclear.Method:Colon tissues from patients with UC were collected to testβ-catenin and Notch1 expression by using Western blot and quantitative real-time polymerase chain reaction(PCR).β-catenin^(fl/fl) mice,β-cateninTg mice,and Dll1tm1 Gos mice were used to cross with Lgr5-EGFP-IRES-creERT2 mice to generate mice of different genotypes,altering the activation of Wnt/β-catenin and Dll1-mediated Notch signaling in ISCs in vivo.Dextran sulfate sodium(DSS)was used to induce a colitis mice model.Intestinal organoids were isolated and cultured to observe the proliferation and differentiation levels of ISCs.Result:β-catenin and Notch1 expression were significantly increased in the inflamed colon tissues from patients with UC.Wnt/β-catenin activation and Dll1-mediated Notch pathway inhibition in Lgr5-positive stem cells promoted the expressions of E-cadherin,CK20,and CHGA in colonic organoids and epithelium,implying the promotion of colonic epithelial integrity.Activation of Wnt/β-catenin and suppression of Dll1-mediated Notch pathway in Lgr5-positive ISCs alleviated the DSS-induced intestinal mucosal inflammation in mice.Conclusions:Lgr5-positive ISCs are characterized by self-renewal and high dividend potential,which play an important role in the injury and repair of intestinal mucosa.More importantly,the Wnt/β-catenin signaling pathway cooperates with the Notch signaling pathway to maintain the function of the Lgr5-positive ISCs.

关 键 词：intestinal stem cell ulcerative colitis LGR5 Β-CATENIN NOTCH 

分 类 号：R73[医药卫生—肿瘤]