E-cadherin acts as a dynamic switch in epithelial regeneration in inflammatory bowel disease.

Abstract

Effective epithelial regeneration is crucial for mucosal healing to achieve complete remission in patients with inflammatory bowel disease (IBD). E-cadherin (Cdh1), a key transmembrane protein mediating epithelial cell-cell adherence, must be transiently suppressed to permit proliferation yet subsequently restored for epithelial maturation. Although its role in cancer and developmental biology has been well studied, the role of E-cadherin in intestinal epithelial repair remains unexplored. Thus, we hypothesize that a temporary reduction in E-cadherin during early repair enhances proliferation, followed by E-cadherin rebound that drives differentiation, improving mucosal healing. When we employed an isopropyl-β-D-thiogalactopyranoside (IPTG)-inducible shRNA lentiviral system to induce Cdh1 knockdown (KD), colonoids developed stem-like spheroidal shapes. This phenotype was supported by upregulated intestinal stem cell (ISC) marker (Lgr5) and increased proliferation (Ki67), along with increased Wnt and Hippo target gene expression levels. Consistently, transcriptomic data further confirmed the significant enrichment of ISC- and fetal-like-associated genes, as well as multiple regeneration-related pathways, in Cdh1 KD colonoids compared with controls. In the novel inflammatory injury and repair model established by combining proinflammatory cytokines and anoxia, IPTG-treated Cdh1 KD during the early regeneration phase enhanced epithelial repair process. Finally, in vivo validation through colonoid transplantation in dextran sulfate sodium-induced colitis mice demonstrated enhanced mucosal healing in the group receiving IPTG-pretreated colonoids compared with those receiving normal colonoids. These findings support a model in which transient, controlled E-cadherin downregulation promotes epithelial repair and may represent a promising therapeutic approach to promote mucosal healing in IBD patients.