E-cadherin loss in intestinal stem cells enhances epithelial regeneration following colitis injury

Chronic inflammation and mucosal injury are hallmarks of the pathogenesis of inflammatory bowel disease (IBD). Current pharmaceutical treatment for IBD-associated symptoms aims to reduce chronic inflammation but fails to address mucosal healing, thereby limiting intestinal regeneration and worsening prognosis for the patient. Intestinal stem cells (ISCs) are essential for regenerating the intestinal epithelial lining, but chronic inflammation can cause them to enter a state of quiescence, or inactivity. While the role of E-cadherin in epithelial proliferation is well characterized in cancer biology, there is limited research on how it influences ISC regeneration after injury. Therefore, we hypothesized that E-cadherin knockout in Lgr5+ ISCs promotes intestinal epithelial expansion and regeneration following colitis injury. The mice for tamoxifen-induced E-cadherin knockout in Lgr5+ ISCs were produced by crossbreeding Lgr5-CreERT and Cdh1fl/fl mice. At the peak of dextran sodium sulfate (DSS)-induced colitis symptoms (day 8), 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 collected to evaluate the severity of injury and degree of recovery between all treatment groups. No significant differences were detected for body weight, DAI, or colon length between the groups. However, E-cadherin homologous knockout during regeneration led to a marked increase in re-epithelization. Simultaneously, the regenerative area was significantly larger in the complete knockout mice compared to the wild type and the heterogeneous group. Immunofluorescence microscopy also revealed an increase in Ki-67+ cells in the regenerative zone of homologous knockout mice. Our results indicate that E-cadherin knockout in ISCs during regeneration results in increased cell expansion, which is crucial to complete mucosal healing following injury. This work identifies E-cadherin as a previously underappreciated regulator of mucosal repair and suggests that transient modulation of E-cadherin in stem cells may represent a therapeutic strategy to enhance regeneration in patients with IBD. This abstract was presented at the American Physiology Summit 2026 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.