This paper details a comprehensive molecular analysis of intestinal fistulae, the penetrating lesions characteristic of Crohn’s disease, using advanced single-cell RNA sequencing and spatial transcriptomics (ST) on tissue samples from 92 individuals. The research defined a unique and abundant cell type called Fistula-Associated Fibroblasts (FAS cells), which are central to the persistence of the disease, unlike the related fibroblasts found in non-fistulating ulcers. These FAS cells organize into distinct spatial niches around the lesion, exhibiting powerful signatures associated with wound healing, tissue invasion, and extensive fibrotic remodeling of the extracellular matrix. The study further identified that specific transcription factors, including OSR2 and TWIST1, control these pathogenic fibroblast functions and promote dysregulated morphogenic signaling pathways. Overall, the findings reveal that the chronic inflammation and structural reprogramming seen in fistulae are maintained by complex, zone-specific macrophage–fibroblast cross-talk and a progression from superficial remodeling to deeper layer, stabilizing fibrosis.

References:

• McGregor C, Qin X, Jagielowicz M, et al. Spatial fibroblast niches define Crohn’s fistulae[J]. Nature, 2025: 1-10.