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Single-cell and spatial transcriptomics of stricturing Crohn's disease highlights a fibrosis-associated network
Lingjia Kong1,2,3, Sathish Subramanian1,3,4,5, Åsa Segerstolpe1
1Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nature Genetics
|June 25, 2025
Summary
This study reveals key cellular and gene expression networks in Crohn's disease (CD) fibrosis, identifying specific immune cells and fibroblasts in intestinal strictures. The findings map genetic risk factors to spatial organization in diseased tissues.
Area of Science:
- Gastroenterology
- Immunology
- Genomics
Background:
- Fibrosis is a significant complication of Crohn's disease (CD), leading to intestinal strictures and functional impairment.
- Current understanding of the mechanisms driving CD fibrosis and effective therapeutic strategies remains limited.
Purpose of the Study:
- To characterize the cellular and molecular networks underlying fibrosis in Crohn's disease.
- To investigate the spatial organization of gene expression and cellular populations within strictured intestinal tissues.
Main Methods:
- Paired single-cell and spatial transcriptomics were performed on 61 samples from patients with CD and 10 controls without inflammatory bowel disease (IBD).
- Analysis focused on identifying immune cells, fibroblasts, and other cell types within intestinal strictures.
- Gene expression patterns were mapped to intestinal biogeography to understand the spatial distribution of genetic risk factors.
Main Results:
- Intestinal strictures in CD showed increased immune cells, including IgG+ plasma cells and CCR7-hi CD4+ T cells, alongside inflammatory fibroblasts.
- Spatial transcriptomics revealed colocalization of key cellular subsets and identified additional cell populations like interstitial cells of Cajal and enteric neurons.
- Genetic risk loci were found to be enriched within specific spatial modules characterized by inflammatory fibroblasts and lymphoid follicles.
Conclusions:
- The study provides a comprehensive transcriptomic and cellular network map of stricturing Crohn's disease.
- It highlights the spatial organization of multicellular genetic risk factors in the context of CD fibrosis.
- These findings offer insights into the mechanisms of CD fibrosis and potential therapeutic targets.
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