Role of E-Cadherin in Intestinal Stem Cells during Epithelial Repair Following Colitis Damage

Mucosal injury is critical for the pathogenesis of inflammatory bowel disease (IBD) and can develop into chronic inflammation. Current pharmaceutical therapeutic options for addressing IBD-associated inflammation are primarily focused on reducing inflammation. Treatment has not yet expanded to address the mucosal healing that is associated with a better prognosis and a reduced risk of surgery. Intestinal stem cells (ISCs) play a crucial role in regenerating epithelial tissue, which is essential for the complete healing of the mucosa. Although E-cadherin is crucial in various epithelial cells and cancers, research into its role in ISCs during regeneration after injury is limited. Therefore, our goal is to investigate E-cadherin's function in ISCs as a potential therapeutic target to promote mucosal healing. In this study, we hypothesized that the knockout of E-cadherin in Lgr5+ ISCs promotes cellular proliferation during regeneration, following colitis damage. The mice for tamoxifen-induced E-cadherin knockout in Lgr5+ ISCs were generated by crossbreeding Lgr5-CreERT and Cdh1fl/fl mice. Following the peak of dextran sodium sulfate (DSS)-induced colitis symptoms, E-cadherin was homologous or heterogeneous knocked out in ISCs through tamoxifen injection (100 mg/kg, three consecutive days) and compared with wild-type. The body weight, disease activity index (DAI), colon length, and histologic analyses were performed to evaluate the severity of injury and repair. No significant differences were observed in body weight, DAI, or colon length across the groups. However, both E-cadherin heterogeneous and homologous knockout during regeneration led to a marked reduction in epithelization. Simultaneously, the regenerative area was significantly larger in the knockout mice compared to the wild type. Additionally, immunofluorescence microscopy revealed an increase in Ki-67+ cells alongside decreased E-cadherin in the regenerative zone. Our findings suggest that E-cadherin knockout in ISCs during regeneration results in increased cell proliferation but does not lead to migration and differentiation, which are crucial to complete mucosal healing. Thus, upcoming research on the transient downregulation of E-cadherin in ISCs during early regeneration seeks to identify potential therapeutic targets for enhancing intestinal regeneration for patients with IBDs. Maryland Stem Cell Research Fund This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.