Single-nuclei RNA-sequencing of human liver samples reveals heterogeneity and compositional changes of biliary epithelial cell subpopulations during the progression of primary sclerosing cholangitis

In primary sclerosing cholangitis (PSC), biliary epithelial cells (BECs) are central targets of inflammatory responses. However, little is known about their composition, function and role in the disease process. Within this project we aim to decipher the characteristics of BECs at different disease stages.

Human liver biopsies and samples from more than 60 individuals, including PSC patients at various disease stages, other liver diseases and healthy controls, were processed by single-nuclei RNA-sequencing. To resolve the location of cell states, spatial transcriptomic techniques were performed.

We identified seven distinct BEC states. Compared to healthy controls, BECs with a progenitor-like phenotype and those with a mature BEC phenotype showed a significant and gradual decline from early to advanced PSC stages. In contrast, BECs characterized by a reactive ductular phenotype exhibited a progressive and significant increase as PSC advanced. Spatial transcriptomic analysis confirmed the presence of this reactive cell state in the portal fibrotic scar regions. Differential gene expression analysis of BECs in PSC compared to healthy controls revealed, among other findings, a significant upregulation of genes involved in the TNF-α signaling pathway. Additionally, interactome analysis suggested enhanced interactions between BECs and macrovascular endothelial cells in PSC.

In this study, we define specific BEC states implicated in the progression of PSC. Our findings provide a comprehensive understanding of the heterogeneity of BECs in different liver disorders and how BECs might interact with other parenchymal and immune cells in the pathogenesis of PSC.

Publication History

Article published online:
20 January 2025