Integrated Single Cell Spatial Analysis Reveals Dysregulated Basal Progenitor Cells in Ulcerative Colitis Pathogenesis: A Multi Omics Study.

[BACKGROUND AND AIMS] Ulcerative colitis (UC), a chronic inflammatory bowel disease, causes persistent mucosal inflammation and epithelial dysfunction. Basal progenitor cells (BPCs), critical for intestinal regeneration and mucosal repair, exhibit altered behavior in UC. Despite extensive research into immune dysregulation, the spatial dynamics and functional roles of BPCs in UC remain poorly understood.

[METHODS] We utilized multi-omics integration, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and machine learning (ML) to analyze BPC dynamics in UC. scRNA-seq data from UC and healthy samples were processed to identify the cellular composition, functional gene matrixes, and differentiation trajectories. ST provided spatial expression patterns, and ML models were used to prioritize key genes associated with disease severity. The prognostic potential for colorectal cancer (CRC) was assessed through external survival analysis.

[RESULTS] Our analysis revealed significant alterations in BPC differentiation in UC, driven by a FABP1-led functional gene matrix. Key genes, including FABP1, CLCA1, ITLN1, MUC2, and TFF1, exhibited spatially distinct expression patterns in UC samples, with FABP1 downregulated and other genes upregulated in BPCs. External survival analyses identified these genes as important biomarkers for both UC and colorectal cancer.

[CONCLUSION] This study uncovers a previously unrecognized role for BPCs in UC pathogenesis, highlighting their spatial dysfunction and potential as a therapeutic target. The identified FABP1-led matrix offers new insights into epithelial dysregulation in UC and its progression to colorectal cancer, suggesting that restoring BPC function may provide novel treatment avenues.