Single-Cell Map of Crohn's Disease Provides New Directions for Drug Development
- This study describes single-cell–level gene expression profiles of 720,633 cells from 46 patients with Crohn's disease (CD) with active or non-inflamed intestinal tissue and 25 individuals without inflammatory bowel disease
- Broad compositional changes were evident across immune and stromal cell subsets, whereas transcriptional reprogramming was more pronounced across epithelial cells
- Some changes were restricted to either the colon or the ileum, suggesting distinct tissue-specific responses
- The data allowed the detection of three regulators of fibroblast collagen induction that may represent novel targets for the management of fibrotic complications in CD, a demonstration of the applicability of the dataset
- The cellular atlas is expected to serve as a framework for further investigation of the complex dysregulation of the gastrointestinal immune response in CD and as a testing ground for disease pathway–specific therapeutic targets
Crohn's disease (CD) primarily affects the terminal ileum and colon, and recent work suggests ileal-dominant CD and colonic CD are separate pathologic subtypes.
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A team at Massachusetts General Hospital has been working to understand what differences there may be in the cellular processes underlying ileal and colonic inflammation.
Using single-cell RNA sequencing (scRNA-seq), the researchers have created a cellular atlas that captures the full complexity of CD. They found that the composition of immune cells and the stroma change during disease; some changes are unique to the ileum or colon. They also discovered that the expression of genes previously linked to CD risk was distinct in the two organs.
Ramnik J. Xavier, MD, PhD, director of the Center for the Study of IBD at Mass General andKurt J. Isselbacher professor of Medicine in the Field of Gastroenterology, Harvard Medical School, and Lingjia Kong, PhD, of the Center for Computational and Integrative Biology and the Department of Molecular Biology at Mass General and instructor in Medicine at Harvard Medical School, and colleagues report the findings in Immunity.
The team collected tissue from 71 patients at Mass General (46 with CD, 25 without inflammatory bowel disease [IBD]). They obtained the samples from three segments of the gastrointestinal tract: 289,730 cells from the colon, 77,554 across the small intestine, and 353,349 specifically from the terminal ileum. Because of the small number of small-bowel cells, they were combined with ileal cells for analyses.
When active disease was present, the researchers collected samples from visibly inflamed and non-inflamed regions. They used scRNA-seq to analyze gene activity in individual gut cells.
Several cell-type–specific changes were detected:
- Epithelial cells evidenced the greatest changes in expression profiles, including a broad increase in the expression of MHC class II genes
- In immune cells, differences in gene expression were comparatively smaller, but their compositional changes were more marked
- Stromal cells displayed both transcriptional and compositional changes, perhaps reflecting joint reprogramming and tissue remodeling
Surprisingly, in all three compartments, transcriptional changes in non-inflamed disease samples were strongly correlated with those in inflamed samples, perhaps indicating signs of disease are detectable even when tissue appears healed on endoscopy.
Understanding the pathways involved in maintaining this ''inflamed-like'' transcriptional network in endoscopically normal tissue might uncover key targets for disease-modifying therapies and, ultimately, curative approaches.
Location-specific changes were also detected. Some changes were restricted to either the ileum or colon, and colonic tissues showed stronger transcriptomic changes in inflammation and disease than those in the ileum.
Leveraging the Data
As a demonstration, the researchers used the transcriptomic results to identify a subset of genes linked to the transition between two fibroblast subsets that are differentially abundant in CD and have differential collagen production characteristics. It was then possible to validate a set of genes—TBX3, RNF168, and CHMP1A—that affect collagen production in those cells.
Those genes may be involved in CD-related fibrosis, and it may be possible to develop therapies to manage that complication. Similar studies focused on other risk genes, and compartments could broadly extend the understanding of functional regulators of CD and identify disease pathway–specific targets.
The cellular atlas is expected to serve as a foundational resource to explore the impact of CD progression and therapeutic strategies, which may differ by disease subtype. The team plans to extend the atlas by collecting samples from patients of a range of ancestries and by obtaining longitudinal samples pre- and post-treatment.
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