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Spatially Resolved Insights Into Fistulating Crohn’s Disease Pathogenesis - scRNA-Seq

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Dataset overview

Participants None
Samples 62
Reuse readiness 6.4/10 evidence-backed score

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, et al. · Nature · 2025

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<sup>1-3</sup>. 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 ↗ PMID 41224999 ↗ PMC12804086 ↗

Study facts

Organism
Homo sapiens
Platform
10x Chromium Single Cell
Age group
adult
Disease groups
—
Anatomical sites
small intestine

Data availability

  • Raw counts

File types TAR

Strengths & limitations for reuse

Strengths

  • Raw reads are advertised
  • Raw counts are advertised

Limitations

  • Not documented: processed matrices are advertised
  • Not documented: cell metadata are advertised
  • Not documented: participant counts are documented
Extraction evidence & provenance

Each extracted field is shown with the source excerpt and location used to resolve it.

Assay

FieldValueEvidence
assay.assay_type single-cell RNA sequencing
Droplet-based scRNA-seq was undertaken using the 10X Chromium Single Cell platform

Section Methods — Droplet-based scRNA-seq, offset —
assay.library_chemistry 5' v1.1 chemistry
10X Genomics, 5’ v1.1 chemistry, CG000208, Rev F

Section Methods — Droplet-based scRNA-seq, offset —
assay.platform 10x Chromium Single Cell
10X Chromium Single Cell platform

Section Methods — Droplet-based scRNA-seq, offset —
assay.reference_genome hg38
Human hg38 (refdata-gex-GRCh38-2020-A) reference genome was used for all alignments and gene annotation

Section Methods — Raw sequencing data processing, offset —
assay.sequencing_type scrna_seq
profiled using single cell RNA-Seq

Section series_overall_design, offset —

Cohort

FieldValueEvidence
cohort.age_group adult
Written informed consent was obtained from adult patients undergoing elective or emergency IBD surgery

Section Methods — Human tissue samples, offset —
cohort.disease_activity_metadata_available True
detailing key demographic and clinical variables such as age, sex, diagnosis, disease subtype, anatomical site, inflammation status and treatment history

Section Supplementary information, offset —
cohort.treatment_exposure_documented True
detailing key demographic and clinical variables such as age, sex, diagnosis, disease subtype, anatomical site, inflammation status and treatment history

Section Supplementary information, offset —

Data_Assets

FieldValueEvidence
data_assets.open_access True
Public on Sep 30 2025

Section series_status, offset —
data_assets.raw_counts True
raw counts matrixes from Cellranger pipeline output

Section —, offset —
data_assets.raw_reads True
GSE284230_RAW.tar

Section —, offset —

Processing

FieldValueEvidence
processing.batch_correction_reported True
Principal components were then further batch-corrected using Harmony

Section Methods — scRNA-seq data analysis, offset —
processing.cell_type_annotation_method canonical marker genes and reference-dataset label transfer
Cell clusters were annotated using a combination of known marker genes and cross-classification with previously published scRNA-seq reference atlas datasets

Section Methods — scRNA-seq data analysis, offset —
processing.doublet_detection_reported True
Doublets were identified as cells positive for multiple tags and filtered out from further analysis

Section Methods — scRNA-seq data analysis, offset —
processing.quality_control_reported True
Cell QC metrics were calculated ... and cell barcodes with low total UMI counts, low complexity and high mitochondrial RNA gene counts were filtered out

Section Methods — scRNA-seq data analysis, offset —

Specimens

FieldValueEvidence
specimens.anatomical_sites ['small intestine']
Small Intestine

Section —, offset —
specimens.inflamed_status_available True
detailing key demographic and clinical variables such as age, sex, diagnosis, disease subtype, anatomical site, inflammation status and treatment history

Section Supplementary information, offset —
specimens.number_of_cells 129204
Our scRNA-seq cohort yielded 129,204 high-quality cells from immune, stromal and epithelial compartments

Section Spatial mapping of fistulating CD, offset —
specimens.number_of_samples 62
"n_samples": 62

Section —, offset —
specimens.specimen_type resection
Full-thickness resection tissue samples, surplus to clinical needs, were obtained by the operating surgeon

Section Methods — Sample collection, handling and processing, offset —