Article ; Online: Multimodal single-cell analyses reveal mechanisms of perianal fistula in diverse patients with Crohn's disease.
Med (New York, N.Y.)
2024
Abstract: Background: Crohn's disease complicated by perianal fistulae is more prevalent and severe in patients of African ancestry.: Methods: We profiled single cells from diverse patients with Crohn's disease with perianal fistula from colorectal mucosa and ... ...
| Abstract | Background: Crohn's disease complicated by perianal fistulae is more prevalent and severe in patients of African ancestry. Methods: We profiled single cells from diverse patients with Crohn's disease with perianal fistula from colorectal mucosa and fistulous tracts. Immunofluorescence was performed to validate predicted cell-cell interactions. Unstimulated monocytes were chronically cultured in diverse cohorts. A subset was analyzed by single-nucleus RNA + ATAC sequencing. Findings: Fistulous tract cells from complete proctectomies demonstrated enrichment of myeloid cells compared to paired rectal tissues. Ligand-receptor analysis highlights myeloid-stromal cross-talk and cellular senescence, with cellular co-localization validated by immunofluorescence. Chitinase-3 like-protein-1 (CHI3L1) is a top upregulated gene in stromal cells from fistulae expressing both destructive and fibrotic gene signatures. Monocyte cultures from patients of African ancestry and controls demonstrated differences in CHI3L1 and oncostatin M (OSM) expression upon differentiation compared to individuals of European ancestry. Activating protein-1 footprints are present in ATAC-seq peaks in stress response genes, including CHI3L1 and OSM; genome-wide chromatin accessibility including JUN footprints was observed, consistent with reported mechanisms of inflammatory memory. Regulon analyses confirm known cell-specific transcription factor regulation and implicate novel ones in fibroblast subsets. All pseudo-bulked clusters demonstrate enrichment of genetic loci, establishing multicellular contributions. In the most significant African American Crohn's genetic locus, upstream of prostaglandin E receptor 4, lymphoid-predominant ATAC-seq peaks were observed, with predicted RORC footprints. Conclusions: Population differences in myeloid-stromal cross-talk implicate fibrotic and destructive fibroblasts, senescence, epigenetic memory, and cell-specific enhancers in perianal fistula pathogenesis. The transcriptomic and epigenetic data provided here may guide optimization of promising mesenchymal stem cell therapies for perianal fistula. Funding: This work was supported by grants U01DK062422, U24DK062429, and R01DK123758. |
|---|---|
| Language | English |
| Publishing date | 2024-04-18 |
| Publishing country | United States |
| Document type | Journal Article |
| ISSN | 2666-6340 |
| ISSN (online) | 2666-6340 |
| DOI | 10.1016/j.medj.2024.03.021 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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