Diversity and heterogeneity in human pancreaticobiliary maljunction revealed by single-cell RNA sequencing.
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PURPOSE: The etiology and pathogenesis of pancreaticobiliary maljunction (PBM) remain unclear, thus a comprehensive investigation of cellular diversity and microenvironmental differences is pivotal to elucidate the mechanisms driving PBM. METHODS: We performed single-cell RNA sequencing on bile duct tissues from six patients, including three with PBM and three without (non-PBM). Pathway enrichment, transcription factor analysis, and cell-cell communication were analyzed to explore cellular interactions and functional states. RESULTS: A total of 90,996 single cells and 11 distinct cell lineages were identified, revealing significant differences in cellular composition between the two groups. PBM group was characterized by a higher proportion of endothelial cells and fibroblasts, while B and T cells were less abundant. Three subtypes of fibroblasts, antigen-presenting, inflammatory, and myofibroblastic cancer-associated fibroblasts, with the myofibroblast subtype being predominant in PBM. We found heightened activity of the WNT and TWEAK signaling pathways in PBM, as well as increased ligand-receptor interactions between fibroblasts and other cell types, including epithelial and endothelial cells. CONCLUSION: Fibroblasts play a central role in driving fibrosis and tissue remodeling in PBM through specific signaling pathways. These insights provide a foundation for future therapeutic strategies aimed at modulating fibroblast activity to prevent or mitigate fibrosis in PBM.