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We demonstrated that a risk variant for Crohn\u2019s disease, hepatocyte growth factor activator (HGFAC) Arg\n            <jats:sup>509<\/jats:sup>\n            His (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 exhibited impaired proteolytic activation of the growth factor macrophage-stimulating protein (MSP). In\n            <jats:italic>Hgfac<\/jats:italic>\n            R509H mice, reduced MSP activation in response to wounding of the colon resulted in impaired WAE cell induction and delayed healing. Through integration of single-cell transcriptomics and spatial transcriptomics, we demonstrated that WAE cells generated RA in a spatially restricted region of the wound site and that mucosal fibroblasts responded to this signal by producing extracellular matrix and growth factors. We further dissected this WAE cell\u2013fibroblast signaling circuit in vitro using a genetically tractable organoid coculture model. Collectively, these studies exploited a genetic perturbation associated with human disease to disrupt a fundamental biological process and then reconstructed a spatially resolved mechanistic model of tissue healing.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adg5252","type":"journal-article","created":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T17:58:22Z","timestamp":1698256702000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":15,"title":["Genetic vulnerability to Crohn\u2019s disease reveals a spatially resolved epithelial restitution program"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3678-4807","authenticated-orcid":true,"given":"Toru","family":"Nakata","sequence":"first","affiliation":[{"name":"Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA."},{"name":"Department of Molecular 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