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Hepatic progenitor cell-originated ductular reactionfacilitates liver fibrosis through activation of hedgehogsignaling

ABSTRACT: Background: It is poorly understood what cellular types participate in ductular reaction (DR) andwhether DR facilitates recovery from injury or accelerates hepatic fibrosis. The aim of this study is to gaininsights into the role of hepatic progenitor cell (HPC)-originated DR during fibrotic progression.Methods: DR in liver specimens of PBC, chronic HBV infection (CHB) or NAFLD, and four rodentfibrotic models by different pathogenic processes was evaluated. Gli1 expression was inhibited in rodentmodels or cell culture and organoid models by AAV-shGli1 or treating with GANT61.Results: Severity of liver fibrosis was positively correlated with DR extent in patients with PBC, CHB orNAFLD. HPCs were activated, expanded, differentiated into reactive cholangiocytes and constituted“HPC-originated DR”, accompanying with exacerbated fibrosis in rodent models of HPC activation &proliferation (CCl4/2-AAF-treated), Μdr2-/- spontaneous PSC, BDL-cholestatic fibrosis orWD-fed/CCl4-treated NASH-fibrosis. Gli1 expression was significantly increased in enriched pathways invivo and in vitro. Enhanced Gli1 expression was identified in KRT19+-reactive cholangiocytes. SuppressingGli1 expression by administration of AAV-shGli1 or GANT61 ameliorated HPC-originated DR andfibrotic extent. KRT19 expression was reduced after GANT61 treatment in sodium butyrate-stimulated WB-F344 cells or organoids or in cells transduced with Gli1 knockdown lentiviral vectors. In contrast,KRT19 expression was elevated after transducing Gli1 overexpression lentiviral vectors in these cells.Conclusions: During various modes of chronic injury, Gli1 acted as an important mediator of HPCactivation, expansion, differentiation into reactive cholangiocytes that formed DR, and subsequentlyprovoked hepatic fibrogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE273215 | GEO | 2025/08/01

REPOSITORIES: GEO

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Project description:Background: As the role of hepatic progenitor cells (HPCs) 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. Methods and Results: We generated HPC-specific Rbpj conditional knockout mice (CKO) using Foxl1-Cre and treated them with the DDC diet to induce chronic liver disease. CKO 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, hepatic stellate cells, 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. Conclusions: Our 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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Hepatic progenitor cell-originated ductular reactionfacilitates liver fibrosis through activation of hedgehogsignaling

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