Spatial fibroblast niches define Crohn’s fistulae

McGregor C, Qin X, Jagielowicz M, Gupta T, Yin Z, Lentsch V, Fawkner-Corbett D, Wien Lai V, Gomez Castro P, Bridges E, Lee CHJ, Chuang HW, Deng L, Aulicino A, Teague R, Moradi S, Park JS, Woo J, Xu K, Tandon R, Cianci N, Bornschein J, Ho LP, Siejka-Zielinska P, Christoforidou Z, Hill S, Lehmann J, Kujawa R, Vargas Gutierrez P, Cheng C, Greco M, Baker K, Bignell M, George B, Fryer E, Vieth M, Antanaviciute A, Simmons A (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Nature Nature Research

Book Volume: 649

Pages Range: 703–712

DOI: 10.1038/s41586-025-09744-y

Abstract

Crohn’s disease often presents with fistulae, abnormal tunnels that connect the intestine to the skin or other organs. Despite their profound effect on morbidity, the molecular basis of fistula formation remains unclear, largely owing to the challenge of capturing intact fistula tracts and their inherent heterogeneity1, 2–3. Here we construct a subcellular-resolution spatial atlas of 68 intestinal fistulae spanning diverse anatomical locations. We describe fistula-associated epithelial, immune and stromal cell states, revealing abnormal zonation of growth factors and morphogens linked to establishment of tunnelling anatomy. We identify fistula-associated stromal (FAS) fibroblasts, which are assembled in concentric layers: a proliferative, lumen-adjacent zone beneath neutrophil and macrophage-rich granulation tissue, an active lesion core of FAS cells and a quiescent, pro-fibrotic outer zone. We examine the architecture of the extracellular matrix in the fistula tract and demonstrate that FAS populations associate with distinct collagen structures, exhibiting properties ranging from proliferation, migration and extracellular matrix remodelling to dense collagen deposition and fibrosis. We define niches supporting epithelialization of fistula tunnels and a FAS-like population that is detected at the base of ulcers in non-penetrating Crohn’s disease. Our study demonstrates that common molecular pathways and cellular niches underpin fistulae across intestinal locations, revealing the cellular protagonists of fistula establishment and persistence. This resource will inform the development of model systems and interventions to mitigate aberrant fibroblast activity while preserving their regenerative properties in Crohn’s disease.

Authors with CRIS profile

Michael Vieth Professur für Allgemeine Pathologie am Medizincampus Oberfranken

Involved external institutions

MRC Weatherall Institute Of Molecular Medicine GB United Kingdom (GB) Oxford University Hospitals NHS Foundation Trust GB United Kingdom (GB) University of Oxford GB United Kingdom (GB)

How to cite

APA:

McGregor, C., Qin, X., Jagielowicz, M., Gupta, T., Yin, Z., Lentsch, V.,... Simmons, A. (2025). Spatial fibroblast niches define Crohn’s fistulae. Nature, 649, 703–712. https://doi.org/10.1038/s41586-025-09744-y

MLA:

McGregor, Colleen, et al. "Spatial fibroblast niches define Crohn’s fistulae." Nature 649 (2025): 703–712.

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