空间成纤维细胞壁龛定义克罗恩瘘管，这一成果由牛津大学Alison Simmons团队经过不懈努力而取得。相关论文于2025年11月12日发表于国际顶尖学术期刊《自然》杂志上。

在这里，研究组构建了跨越不同解剖位置的68个肠瘘的亚细胞分辨率空间图谱。课题组研究人员描述了瘘相关的上皮、免疫和基质细胞状态，揭示了与隧道解剖学建立相关的生长因子和形态因子的异常分带。该课题组人员确定了瘘相关基质（FAS）成纤维细胞，它们聚集在同心层中：在中性粒细胞和巨噬细胞丰富的肉芽组织下的增生，腔邻近区，FAS细胞的活跃病变核心和静止的促纤维化外区。

该团队研究了瘘道中细胞外基质的结构，并证明FAS群体与不同的胶原结构相关，表现出从增殖、迁移和细胞外基质重塑到致密胶原沉积和纤维化的特性。研究小组定义了支持瘘管通道上皮化的壁龛和在非穿透性克罗恩病溃疡底部检测到的FAS样人群。他们的研究表明，共同的分子途径和细胞生态位支撑着跨越肠道部位的瘘管，揭示了瘘管建立和持续存在的细胞主角。这种抵抗将为模型系统和干预措施的发展提供信息，以减轻克罗恩病中异常成纤维细胞的活性，同时保持其再生特性。

据介绍，克罗恩病通常表现为瘘管，即连接肠道与皮肤或其他器官的异常隧道。尽管它们对发病率有深远的影响，但瘘管形成的分子基础仍不清楚，这主要是由于捕获完整的瘘管束及其固有的异质性所带来的挑战。

附：英文原文

Title: Spatial fibroblast niches define Crohn’s fistulae

Author: McGregor, Colleen, Qin, Xiao, Jagielowicz, Marta, Gupta, Tarun, Yin, Zinan, Lentsch, Verena, Fawkner-Corbett, David, Wien Lai, Vy, Gomez Castro, Paula, Bridges, Esther, Lee, Chloe Hyun-Jung, Chuang, Huei-Wen, Deng, Lei, Aulicino, Anna, Teague, Renuka, Moradi, Sorayya, Park, Jun Sung, Woo, Jeongmin, Xu, Kexin, Tandon, Ruchi, Cianci, Nicole, Bornschein, Jan, Ho, Ling-Pei, Siejka-Zielinska, Paulina, Christoforidou, Zoe, Hill, Sarah, Lehmann, Johannes, Kujawa, Rhea, Vargas Gutierrez, Paola, Cheng, Carol, Greco, Maria, Baker, Katherine, Bignell, Mark, George, Bruce, Fryer, Eve, Vieth, Michael, Antanaviciute, Agne, Simmons, Alison

Issue&Volume: 2025-11-12

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.

DOI: 10.1038/s41586-025-09744-y

Source: https://www.nature.com/articles/s41586-025-09744-y