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Spatially Resolved Insights Into Fistulating Crohn’s Disease Pathogenesis - Visium Spatial Transcriptomics

ABSTRACT: Crohn's disease often presents with fistulae, abnormal tunnels connecting the intestine to the skin or other organs. Despite the profoundly adverse impact of fistulae on patient morbidity, the molecular basis of their formation remains unclear, largely due to the challenge of capturing intact fistula tracts and their inherent heterogeneity. Here, we construct an unbiased, subcellular-resolution spatial expression atlas of 62 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 identified fistula-associated stromal (FAS) fibroblasts assembled in concentric layers, forming a proliferative, lumen-adjacent zone (LAZ) underlying surface neutrophil and macrophage-rich granulation tissue, followed by active lesion core FAS cells all encircled by quiescent, pro-fibrotic outer zone (FOZ) fibroblasts. We mapped fistula tract ECM architecture and demonstrated FAS populations locate to different collagen structures, exhibiting functional properties spanning proliferation, migration and active ECM remodelling, to dense collagen deposition and fibrosis. We define niches supporting epithelialization of fistula tunnels and a putative precursor FAS population detected at the base of ulcers in non-penetrating Crohn’s. This precursor population co-localises with inflammatory as opposed to pro-fibrotic SPP1+ macrophages and fails to induce developmental transcription factors, observed in FAS populations located in fistula tracts. Our study demonstrates that common molecular pathways and cellular niches underpin fistulae arising at different intestinal locations and reveal the cellular protagonists of fistula establishment and persistence. Our resource will inform development of model systems and interventions that mitigate aberrant fibroblast activity while preserving their regenerative properties in Crohn’s.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283945 | GEO | 2025/09/30

REPOSITORIES: GEO

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Project description:Crohn's disease often presents with fistulae, abnormal tunnels connecting the intestine to the skin or other organs. Despite the profoundly adverse impact of fistulae on patient morbidity, the molecular basis of their formation remains unclear, largely due to the challenge of capturing intact fistula tracts and their inherent heterogeneity. Here, we construct an unbiased, subcellular-resolution spatial expression atlas of 62 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 identified fistula-associated stromal (FAS) fibroblasts assembled in concentric layers, forming a proliferative, lumen-adjacent zone (LAZ) underlying surface neutrophil and macrophage-rich granulation tissue, followed by active lesion core FAS cells all encircled by quiescent, pro-fibrotic outer zone (FOZ) fibroblasts. We mapped fistula tract ECM architecture and demonstrated FAS populations locate to different collagen structures, exhibiting functional properties spanning proliferation, migration and active ECM remodelling, to dense collagen deposition and fibrosis. We define niches supporting epithelialization of fistula tunnels and a putative precursor FAS population detected at the base of ulcers in non-penetrating Crohn’s. This precursor population co-localises with inflammatory as opposed to pro-fibrotic SPP1+ macrophages and fails to induce developmental transcription factors, observed in FAS populations located in fistula tracts. Our study demonstrates that common molecular pathways and cellular niches underpin fistulae arising at different intestinal locations and reveal the cellular protagonists of fistula establishment and persistence. Our resource will inform development of model systems and interventions that mitigate aberrant fibroblast activity while preserving their regenerative properties in Crohn’s.

Project description:Background: Crohn’s disease is presently an incurable inflammatory bowel disease. Fistulae are extensions of the intestinal tract that may form connections with other organs. These are a common complication of Crohn’s disease affecting up to 50% of patients with the most common including perianal and rectovaginal fistulae. The dysregulated growth observed in fistulae shares several major characteristics seen in the development of tumours. These similarities include epithelial-to-mesenchymal transition (EMT), invasive cell growth, increased extracellular matrix production and remodelling, up-regulated local expression of growth factors such as IGF-1 and the down-regulation of apoptosis pathways. Although several susceptibility loci have been described within Crohn’s disease there is no individual gene or mutation that identifies susceptibility or the subsequent formation of fistulae within all people. Copy-number variation (CNV) is one mechanism that may explain much of this genetic complexity. CNV may be caused by a variety of mechanisms such as cycles of chromosomal breakage/fusion/bridging that are typical within chronically inflamed tissue. Interestingly CNV shows locus-specific mutation rates between individuals higher than that of SNPs and has been associated with complex Mendelian traits including disease susceptibility. In this current study we performed array comparative genomic hybridisation (aCGH) analysis of active fistulae resected from patients as part of a previous surgical intervention. As the control for comparison we employed tissue taken from the same patient within the same surgery at an uninvolved site of the gastrointestinal tract. This matched control was employed to better investigate CNV specific to the fistula tissue of each individual avoiding complications associated with the large number of CNV present within the healthy population. Major question addressed by the work: What are the differences in genetic copy-number within localised intestinal fistula tissue of individuals with Crohn’s disease compared to healthy intestinal tissue from the same individual?

Project description:Background: CrohnM-bM-^@M-^Ys disease is presently an incurable inflammatory bowel disease. Fistulae are extensions of the intestinal tract that may form connections with other organs. These are a common complication of CrohnM-bM-^@M-^Ys disease affecting up to 50% of patients with the most common including perianal and rectovaginal fistulae. The dysregulated growth observed in fistulae shares several major characteristics seen in the development of tumours. These similarities include epithelial-to-mesenchymal transition (EMT), invasive cell growth, increased extracellular matrix production and remodelling, up-regulated local expression of growth factors such as IGF-1 and the down-regulation of apoptosis pathways. Although several susceptibility loci have been described within CrohnM-bM-^@M-^Ys disease there is no individual gene or mutation that identifies susceptibility or the subsequent formation of fistulae within all people. Copy-number variation (CNV) is one mechanism that may explain much of this genetic complexity. CNV may be caused by a variety of mechanisms such as cycles of chromosomal breakage/fusion/bridging that are typical within chronically inflamed tissue. Interestingly CNV shows locus-specific mutation rates between individuals higher than that of SNPs and has been associated with complex Mendelian traits including disease susceptibility. In this current study we performed array comparative genomic hybridisation (aCGH) analysis of active fistulae resected from patients as part of a previous surgical intervention. As the control for comparison we employed tissue taken from the same patient within the same surgery at an uninvolved site of the gastrointestinal tract. This matched control was employed to better investigate CNV specific to the fistula tissue of each individual avoiding complications associated with the large number of CNV present within the healthy population. Major question addressed by the work: What are the differences in genetic copy-number within localised intestinal fistula tissue of individuals with CrohnM-bM-^@M-^Ys disease compared to healthy intestinal tissue from the same individual? Samples were selected from patients presenting with CrohnM-bM-^@M-^Ys Disease fistulae at Eastern Health Department of Gastroenterology and Hepatology (Arnold Street, Box Hill, Victoria, Australia). The 8 samples used in this study were formalin-fixed paraffin-embedded (FFPE) specimens following a surgical intervention to remove fistula tissue. To focus on changes within the individual patient we used tissue taken from the same surgery at an uninvolved region of the intestine as the matched control for CNV analysis.

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Spatially Resolved Insights Into Fistulating Crohn’s Disease Pathogenesis - Visium Spatial Transcriptomics

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