Conserved ductular reaction mechanisms in biliary atresia and PSC derived from single-cell and spatial transcriptomics

Primary sclerosing cholangitis (PSC) and biliary atresia (BA) both demonstrate the ductular reaction (DR), including biliary ductules, immune infiltration, and fibroblast activation. Advances in single-cell RNA sequencing and spatial transcriptomics have revolutionised our understanding of the DR fibro-inflammatory niche of these disorders. Recent studies using these techniques have also demonstrated that there are conserved mechanisms of fibro-inflammation across diseases and organ systems. Notably, epithelial, mesenchymal, and innate immune processes in the DR are shared between BA and PSC, including: pro-fibrogenic hepatocyte-to-cholangiocyte transdifferentiation, increased cholangiocyte senescence, accumulation of scar-/lipid-associated macrophages, Kupffer cell dysfunction, and activation of portal fibroblasts. In contrast, adaptive immune processes differ between the two disorders, including: transdifferentiation of Th17 into Th1 cells in BA, dominance of the Th17 axis in PSC, reduced CX3CR1 CD8/NKT-cells in BA, and gut-priming with liver-homing of lymphocytes in PSC. Future work needs to include a range of early- and late-stage disease samples, particularly non-cirrhotic PSC, and the use of single-cell spatial transcriptomic technologies will allow higher confidence in prediction of ligand-receptor interactions. These observations facilitate identification of therapeutic targets against conserved mechanisms of the DR applicable to multiple fibro-inflammatory disorders.