%0 Journal Article
%T Multimodal single-cell analyses reveal mechanisms of perianal fistula in diverse patients with Crohn's disease.
%A Levantovsky RM
%A Tastad C
%A Zhang J
%A Gettler K
%A Sabic K
%A Werner R
%A Chasteau C
%A Korie U
%A Paguay D
%A Bao M
%A Han H
%A Maskey N
%A Talware S
%A Patel M
%A Argmann C
%A Suarez-Farinas M
%A Harpaz N
%A Chuang LS
%A Cho JH
%J Med
%V 5
%N 8
%D 2024 Aug 9
%M 38663404
暂无%R 10.1016/j.medj.2024.03.021
%X 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.
RESULTS: 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.
BACKGROUND: This work was supported by grants U01DK062422, U24DK062429, and R01DK123758.