Precisely Modulated E-Cadherin Unlocks Pro-Regenerative Signaling Pathways, Accelerating Mucosal Healing in Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis, are chronic relapsing disorders characterized by epithelial barrier loss and incomplete mucosal repair. Although current therapies suppress inflammation, they rarely achieve durable mucosal healing, highlighting a need for epithelial-targeted strategies that enhance intestinal regeneration. Intestinal stem cells (ISCs) are central to epithelial renewal, yet the signals that coordinate their activation during inflammatory injury remain poorly defined. E-cadherin, a core adherens junction protein, maintains epithelial polarity and barrier integrity while anchoring key signaling mediators such as β-catenin and YAP/TAZ. Its dysregulation is implicated in tissue injury, regeneration, and tumorigenesis, yet the context-dependent roles of E-cadherin in mucosal healing remain poorly explored. Here, we used an IPTG-inducible Cdh1 shRNA system in colonoids to investigate how transient E-cadherin loss reprograms epithelial regeneration. Knockdown of E-cadherin produced enlarged, cystic colonoids with increased expression of stemness, Wnt/β-catenin, and Hippo/YAP pathway genes, indicating activation of a regenerative, fetal-like transcriptional state. Gene ontology and pathway analyses further revealed enrichment of inflammatory responses, lipid metabolism, and signal transduction, suggesting broad epithelial reprogramming. Using a newly established cytokine/anoxia injury model that mimics the inflammatory and hypoxic conditions of IBD, we demonstrated that temporary E-cadherin suppression during early regeneration enhanced colonoid growth and increased bud formation. Importantly, in a DSS-induced colitis model, transplantation of IPTG-pretreated colonoids harboring transient E-cadherin knockdown significantly improved epithelial restoration and reduced denuded mucosal areas compared with control colonoids. These findings demonstrate that short-term modulation of E-cadherin enhances epithelial plasticity and regeneration without promoting uncontrolled growth. While E-cadherin is indispensable for maintaining barrier homeostasis, its transient downregulation after injury appears to “unlock” pro-regenerative signaling that accelerates mucosal healing. This work identifies E-cadherin modulation as a promising therapeutic approach to restore epithelial integrity and achieve durable remission in 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.