2. Academic Validation
  3. VIPR1 acts as an enteric neural checkpoint that suppresses intestinal stem cell-driven epithelial regeneration and exacerbates colitis

VIPR1 acts as an enteric neural checkpoint that suppresses intestinal stem cell-driven epithelial regeneration and exacerbates colitis

  • Cell Stem Cell. 2026 Mar 5;33(3):502-516.e7. doi: 10.1016/j.stem.2026.01.009.
Chaoliang Li 1,  Haohao Wang 1,  Panrui Zhang 2,  Jianbo Yang 3,  Chao Ye 3,  Xiaowei Wei 2,  Yuchen Zhou 2,  Zhentao Yang 2,  Dan Cao 1,  Kaiguang Zhang 3,  Rongbin Zhou 2,  Shu Zhu 2,  Wen Pan 4
Affiliations

Affiliations

  • 1 Department of Digestive Disease, The First Affiliated Hospital of USTC, State Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
  • 2 Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
  • 3 Department of Digestive Disease, The First Affiliated Hospital of USTC, State Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
  • 4 Department of Digestive Disease, The First Affiliated Hospital of USTC, State Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Electronic address: [email protected].
PMID: 41734764 DOI: 10.1016/j.stem.2026.01.009
Abstract

Intestinal stem cells (ISCs) drive epithelial renewal and regeneration, yet how neural cues shape ISC behavior remains unclear. Here, we identify a neuronal checkpoint that directly restrains ISC regenerative output during injury. We show that vasoactive intestinal peptide (VIP)-producing enteric neurons directly signal to ISCs through the epithelial receptor VIP receptor 1 (VIPR1). In steady state, VIP-VIPR1 signaling restrains ISC hyperproliferation by engaging an extracellular signal-regulated kinase (ERK)-Notum-Wnt/β-catenin inhibitory axis. During colitis, VIPergic neurons expand within the ulcerated regions and amplify this pathway, thereby suppressing ISC-driven regeneration and exacerbating epithelial injury. Selective deletion of Vipr1 in the epithelium or in ISCs releases this neuronal brake, restores early regenerative activity, and markedly alleviates colitis. The ISC-suppressive function of VIP-VIPR1 signaling is conserved in human intestinal models. Together, these findings define VIPR1 as an ISC-intrinsic neuronal checkpoint that restricts ISC-driven epithelial regeneration and highlight epithelial VIPR1 blockade as a potential strategy to enhance mucosal regeneration in colitis.

Keywords

Notum; WNT signaling; epithelial regeneration; gut-innervating neurons; inflammatory bowel disease; intestinal stem cells; neuron-epithelial interaction.

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