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.

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 test β-catenin and Notch1 expression by using Western blot and quantitative real-time polymerase chain reaction (PCR). mice, mice, and mice were used to cross with mice to generate mice of different genotypes, altering the activation of Wnt/β-catenin and Dll1-mediated Notch signaling in ISCs . 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.