Nestin + fibroblasts restrain intestinal epithelial regeneration through an IGFBP5–EGFR signalling axis during colitis

Background Fibroblasts are key components of the intestinal stem cell niche, yet their functional heterogeneity and context-dependent roles in inflammatory bowel disease (IBD) remain poorly defined. Objective This study examined the alterations and roles of fibroblasts in intestinal inflammation, focusing on the underlying mechanisms and exploring their therapeutic potential. Design Single-cell RNA sequencing of colonic stromal cells from healthy and colitis mice was used to characterise fibroblast alterations. RNA-seq and organoid assays identified functional factors, while conditional knockout mice were generated to assess the cellular origin and target gene function. In vitro experiments were performed to elucidate the underlying mechanisms. Results Here, we identified a previously unrecognised subset of intestinal fibroblasts marked by Nestin that expands significantly during colitis and unexpectedly acts as a potent inhibitor of epithelial regeneration. We show that Nestin+ fibroblasts proliferate under the mediation of TGFβ signalling and suppress intestinal stem cell self-renewal by secreting insulin-like growth factor binding protein 5 (IGFBP5). Mechanistically, IGFBP5 acts as a non-canonical ligand of EGFR, antagonising EGFR-STAT3 signalling in intestinal epithelial cells and limiting regenerative responses. Therapeutic blocking IGFBP5 and EGFR interaction using an anti-IGFBP5 antibody restored epithelial regeneration and significantly relieves colitis. Conclusions Our findings uncover an inhibitory stromal–epithelial signalling axis that restrains intestinal repair during inflammation and identify IGFBP5 as a promising therapeutic target for promoting mucosal healing in IBD.