This study integrates single-cell and spatial transcriptomic techniques to systematically dissect the cellular composition, gene expression profiles, and spatial organization associated with intestinal fibrosis in Crohn's disease (CD). It identifies specific fibroblast subpopulations, expansion of tertiary lymphoid structures, and their spatial co-localization with immune cells, offering a valuable resource for developing fibrosis-targeted therapeutic strategies.
Literature Overview
This paper, titled 'Single-cell and spatial Transcriptomics of Stricturing Crohn’s Disease Highlights a Fibrosis-Associated Network', published in Nature Genetics, reviews and summarizes the cellular heterogeneity, gene expression changes, and spatial organization of intestinal strictures from 61 tissue samples of CD patients. The study reveals significant expansion of IgG+ plasma cells, CCR7-hi CD4+ T cells, and inflammatory fibroblasts in fibrotic tissues, along with the formation of tertiary lymphoid structures. Furthermore, it demonstrates that known CD risk genes are enriched in distinct spatial modules, suggesting their functional importance within localized microenvironments.
Background Knowledge
Crohn’s disease is a chronic inflammatory bowel disease (IBD), one of whose complications is intestinal fibrosis, eventually leading to clinical issues such as bowel strictures and intestinal obstruction. Currently, no effective drugs exist to reverse fibrosis, and surgical resection remains the only option. Fibrosis involves excessive extracellular matrix deposition mediated by fibroblasts, yet the cellular and molecular mechanisms remain incompletely understood. Traditional mouse models poorly recapitulate human CD-related fibrosis, necessitating high-resolution human tissue omics data. Recent advances in single-cell sequencing (scRNA-seq) and spatial transcriptomics (e.g., Visium) have provided new insights into the microenvironment of complex tissues, with widespread applications in inflammation, cancer, and neurodegenerative diseases. This study fills the gap in multi-omic spatial mapping of stricturing CD, offering a foundational understanding of cellular interaction networks and spatial gene expression patterns associated with fibrosis.
Research Methods and Experiments
The study analyzed 61 intestinal tissue samples (from colon and ileum) obtained from 21 CD patients and 10 non-IBD controls using both single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. Researchers performed cellular composition analysis using Bray-Curtis dissimilarity and Dirichlet regression models after separating epithelial and non-epithelial components. An Inflammation-Associated Fibroblast (IAF) score was developed to quantify fibroblast activity associated with fibrosis. Spatial transcriptomics was conducted using Visium technology on 20 surgical samples, followed by spatial deconvolution analysis integrating scRNA-seq data to identify spatial gene expression patterns within the tissue microenvironment.
Key Conclusions and Perspectives
Research Significance and Prospects
This study presents the first comprehensive single-cell and spatial transcriptomic atlas of stricturing Crohn’s disease, revealing key cellular interactions and spatial gene expression networks involved in fibrosis. These findings offer novel insights into targeting cell-cell communication and gene expression in the fibrotic microenvironment. Future studies may combine multi-omics and spatial analysis to further elucidate the dynamic gene regulatory networks in Crohn’s disease and aid in the development of personalized therapeutic approaches.
Conclusion
This study systematically mapped the co-localization patterns of fibroblasts and immune cells, along with their gene expression features, in fibrotic Crohn’s disease tissues using integrated single-cell and spatial transcriptomic approaches. It was found that IL11+ inflammatory fibroblasts and collagen-high fibroblasts occupy distinct spatial niches, suggesting potentially divergent developmental trajectories or functional states. Moreover, CD risk genes show spatial enrichment in specific microenvironments—for example, ITLN1 and GPR35 are induced at the interface between T cells and intestinal epithelial cells—indicating that their expression is regulated by local cellular interactions. This work provides a critical resource for understanding the cellular and molecular underpinnings of Crohn’s disease fibrosis, paving the way for future development of spatially-targeted therapeutic interventions.
