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Here, we quantify the stromal response to inflammation in pediatric IBD and reveal subset-specific inflammatory responses across colon segments and intestinal layers. Using data from a murine dynamic gut injury model and human ex vivo transcriptomic, protein and spatial analyses, we report that PDGFRA<jats:sup>+<\/jats:sup>CD142<jats:sup>\u2212<\/jats:sup><jats:sup>\/low<\/jats:sup> fibroblasts and monocytes\/macrophages co-localize in the intestine. In primary human fibroblast-monocyte co-cultures, intestinal PDGFRA<jats:sup>+<\/jats:sup>CD142<jats:sup>\u2212<\/jats:sup><jats:sup>\/low<\/jats:sup> fibroblasts foster monocyte transition to CCR2<jats:sup>+<\/jats:sup>CD206<jats:sup>+<\/jats:sup> macrophages through granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocyte-derived CCR2<jats:sup>+<\/jats:sup>CD206<jats:sup>+<\/jats:sup> cells from co-cultures have a phenotype similar to intestinal CCR2<jats:sup>+<\/jats:sup>CD206<jats:sup>+<\/jats:sup> macrophages from newly diagnosed pediatric IBD patients, with high levels of PD-L1 and low levels of GM-CSF receptor. The study describes subset-specific changes in stromal responses to inflammation and suggests that the intestinal stroma guides intestinal macrophage differentiation.<\/jats:p>","DOI":"10.1038\/s41467-024-46076-3","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T15:02:14Z","timestamp":1708959734000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Intestinal stroma guides monocyte differentiation to macrophages through 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