ArticleHepatology communications2025
Rbpj deletion in hepatic progenitor cells attenuates endothelial responses and fibrosis in DDC-fed mice.
Article in Hepatology communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundAs the role of hepatic progenitor cells (HPCs) in constituting ductular reactions in pathogenesis remains ambiguous, we aimed to establish the in vivo cause-and-effect relationship between HPCs and chronic liver disease progression. We previously demonstrated that peritumoral ductules are associated with angiogenesis in liver tumors, and forkhead box L1 (Foxl1)-expressing murine HPCs secrete angiogenic factors in vitro. Therefore, we hypothesized that HPCs are capable of remodeling the portal vascular microenvironment and regulating overall liver disease progression, and this function of HPCs is dependent on recombination signal binding protein for immunoglobulin kappa J region (RBPJ), a key effector of the Notch signaling pathway.
methodsWe generated HPC-specific Rbpj conditional knockout mice (CKO) using Foxl1-Cre, treated them with the DDC diet to induce chronic liver disease, and performed serum biochemistry, gene expression analysis, and immunostaining analysis.
resultsCKO mice exhibited a significant reduction in serum levels of liver injury markers, ductular reactions, vascular and fibrotic areas, and hepatic expression of fibrosis and inflammation markers compared to control mice (WT). Single-nucleus RNA sequencing comparing CKO and WT livers detected transcriptome changes across multiple cell types, including endothelial cells, HSCs, and cholangiocytes. Expression of several reactive cholangiocyte markers, including vascular cell adhesion molecule 1 (VCAM1), in HPCs was significantly downregulated in response to anti-Rbpj shRNAs in vitro. Immunofluorescence analysis indicated that the percentage of VCAM1+ cells was reduced in both HPC and cholangiocyte populations in CKO compared to WT in vivo.
conclusionsOur findings reveal Rbpj-dependent expression of reactive cholangiocyte markers in HPCs and demonstrate that Rbpj deletion in HPCs attenuates not only endothelial responses but also liver injury, fibrosis, and VCAM1 expression in cholangiocytes, highlighting the crucial role of HPCs in pathogenic progression.
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