Spatial fibroblast niches define Crohn’s fistulae

作者：Colleen GC McGregor, Xiao Qin, Marta Jagielowicz, Tarun Gupta, Zinan Yin, Verena Lentsch, David Fawkner-Corbett, Vesta Lai, Paula Gomez Castro, Esther Bridges, Chloe H. Lee, Huei-Wen Chuang, Lei Deng, Anna Aulicino, Renuka Teague, S. Moradi, Jun Sung Park, Jeongmin Woo, Kexin Xu, Ruchi Tandon, Nicole Cianci, Jan Bornschein, Ling‐Pei Ho, Paulina Siejka-Zielińska, Zoe Christoforidou, Sarah Hill, Johannes Lehmann, Rhea Kujawa, Paola Vargas Gutierrez, Carol E. Cheng, Maria Greco, Katherine Baker, Mark Bignell, Bruce George, Eve Fryer, Michael Vieth, Agne Antanaviciute, Alison Simmons · 发表于：Nature · 年份：2025 · DOI：10.1038/s41586-025-09744-y · 被引用次数：12 · 研究领域：Inflammatory Bowel Disease、Anorectal Disease Treatments and Outcomes、Autoimmune and Inflammatory Disorders

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 heterogeneity 1–3 . 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, r...