biostudies-literatureNakata TNIDDK NIH HHSNCI NIH HHSeadg5252https://www.ebi.ac.uk/biostudies/studies/S-EPMC10798370biostudies-literatureUnknown15(719)Effective tissue repair requires coordinated intercellular communication to sense damage, remodel the tissue, and restore function. Here, we dissected the healing response in the intestinal mucosa by mapping intercellular communication at single-cell resolution and integrating with spatial transcriptomics. We demonstrated that a risk variant for Crohn's disease, hepatocyte growth factor activator (HGFAC) Arg⁵⁰⁹His (R509H), disrupted a damage-sensing pathway connecting the coagulation cascade to growth factors that drive the differentiation of wound-associated epithelial (WAE) cells and production of a localized retinoic acid (RA) gradient to promote fibroblast-mediated tissue remodeling. Specifically, we showed that HGFAC R509H was activated by thrombin protease activity but exhScience translational medicineGenetic vulnerability to Crohn's disease reveals a spatially resolved epithelial restitution program.PMC10798370P30 CA008748RC2 DK114784P30 DK043351Diamond ELJaiswal ALi CSegerstolpe ADaly MJLu ZMayassi TXavier RJCreasey EAGhosh KBiancalani TNakata THerbst PLefkovith ALin HGaddam SParkar SLi BGraham DBfalseGenetic vulnerability to Crohn's disease reveals a spatially resolved epithelial restitution program.Effective tissue repair requires coordinated intercellular communication to sense damage, remodel the tissue, and restore function. Here, we dissected the healing response in the intestinal mucosa by mapping intercellular communication at single-cell resolution and integrating with spatial transcriptomics. We demonstrated that a risk variant for Crohn's disease, hepatocyte growth factor activator (HGFAC) Arg⁵⁰⁹His (R509H), disrupted a damage-sensing pathway connecting the coagulation cascade to growth factors that drive the differentiation of wound-associated epithelial (WAE) cells and production of a localized retinoic acid (RA) gradient to promote fibroblast-mediated tissue remodeling. Specifically, we showed that HGFAC R509H was activated by thrombin protease activity but exh2023-01-01T00:00:00Z2023 Oct2026-06-02T02:23:22.633Z2025-04-04T19:21:57.373ZS-EPMC107983703787867210.1126/scitranslmed.adg5252