Liver sinusoidal endothelial cells and laminin dictate cholangiocytes’ fate in chronic liver disease
(2026) Journal of Hepatology — Vol. on line S0168-8278, p. 1-14 (2026)
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- Background & aims: In chronic liver diseases (CLD), when native hepatocytes enter replicative senescence, new hepatocytes are generated through differentiation of reactive cholangiocytes, also known as ductular reaction (DR). However, this mechanism alone is insufficient to prevent liver failure, highlighting the need for a deeper understanding to enhance its therapeutic potential. We hypothesize that signals driving DR reside in the local niche, particularly in extracellular matrix composition and neighboring cells. Method: We modeled CLD in mice using carbon tetrachloride injections (3x/week for 6 weeks). Using Opn-iCreERT2; Rosa26RYFP mice, we tracked DR fate, and with Cdh5-iCreERT2; Rosa26RmT/mG mice, we investigated liver sinusoidal endothelial cell (LSEC) lineage and contributions. Mouse liver tissues were analyzed using immunohistochemistry, flow cytometry, reverse-transcription quantitative PCR and Resolve molecular cartography for spatial transcriptomics. Double spheroids were used to study extracellular matrix effects in vitro. Human liver tissues were examined using double immunohistochemistry, and publicly available single-cell RNA-sequencing datasets were analyzed. Results: We identified two populations of ductular reaction (DR) cells: those surrounded by laminin (Lam-DRs) and those lacking laminin (NoLam-DRs). Lam-DRs retained a biliary phenotype, while NoLam-DRs showed increased Hnf4α expression. In vitro, a laminin-rich environment maintained cholangiocyte-specific gene expression, supporting the role of laminin in preserving the biliary phenotype. Lam-DRs were closely associated with capillarized CD34+ LSECs, which expressed profibrotic and laminin-related genes. Preventing LSEC capillarization reduced laminin deposition and enhanced DR-to-hepatocyte differentiation in chronically injured mice. The CD34+ LSEC-laminin-DR complex was also present in human liver disease samples. Conclusion: Capillarized CD34+ LSECs maintain the biliary phenotype of DR cells by preventing laminin degradation, thereby limiting their differentiation into hepatocytes. Targeting this axis could enhance liver regeneration and improve outcomes in CLD. Impact and implications: Chronic liver disease progression is characterized by impaired hepatocyte regeneration, making alternative regenerative pathways, such as ductular reaction-driven hepatocyte formation, of particular interest. This study provides mechanistic insight into how the local microenvironment, specifically capillarized CD34+ liver sinusoidal endothelial cells and laminin deposition, restricts DR plasticity by stabilizing a biliary fate, thereby limiting endogenous regeneration. These findings are relevant for researchers investigating liver regeneration, fibrosis, and cholangiopathies, and for clinicians seeking to understand why regenerative responses remain inefficient in advanced disease. While acknowledging that ductular reaction-derived hepatocytes contribute modestly to overall parenchymal renewal, our results suggest that therapeutically modulating liver sinusoidal endothelial cell capillarization or extracellular matrix remodeling could represent a strategy to enhance regenerative competence in chronic liver disease, warranting further preclinical and translational investigation.
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Manco, R., Moliterni, C., Neirynck, E., Claus, R., De Rudder, M., Picalausa, C., Ducor, L., Fraga, M., Coubeau, L., Dongier, A., Baldin, P., Lemaigre, F., Sempoux, C., Dili, A., & Leclercq, I. (2026). Liver sinusoidal endothelial cells and laminin dictate cholangiocytes’ fate in chronic liver disease. Journal of Hepatology, on line S0168-8278, 1-14. https://doi.org/10.1016/j.jhep.2026.03.022 (Original work published 2026)