Elucidating a Myofibroblast-dominated Fibrotic Niche in Crohn’s Disease-associated Fibrostenosis Through High-resolution Spatial Transcriptomics

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BACKGROUND & AIMS: Fibrostenosis is a major complication of Crohn's disease (CD) characterized by intestinal remodeling and excessive extracellular matrix (ECM) deposition. A prominent feature is bowel wall muscularization, involving expansion of submucosal myoid cells and muscularis propria smooth muscle cell (SMC) hyperplasia. However, the cellular identity and molecular mechanisms underlying submucosal myoid cell hyperplasia remain poorly characterized. METHODS: Preoperative intestinal ultrasound from 117 patients with CD was retrospectively reviewed, and ileal tissues from 25 normal, 35 nonstenotic CD, and 44 stenotic CD cases were analyzed histologically. High-resolution spatial transcriptomics was applied to 1 nonfibrotic and 1 fibrostenotic ileal specimen with marked submucosal myoid cell expansion. Findings were validated using public single-cell RNA sequencing datasets (N = 158), immunofluorescence, primary pericyte cultures, and quantitative polymerase chain reaction. RESULTS: fibroblasts enriched specifically in fibrotic regions. Inflammatory monocytes colocalized with stromal cells, exhibiting robust predicted ligand-receptor interactions indicative of immune-stromal crosstalk. CONCLUSIONS: This case-level, high-resolution spatial analysis delineates a spatially organized fibrotic niche within a CD stricture, composed of distinct stromal and immune populations. We define the identity and origins of profibrotic myofibroblasts and characterize pericyte-to-myofibroblast reprogramming, thereby highlighting specific cell subtypes as prime therapeutic targets for antifibrotic strategies.

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