Liver sinusoidal endothelial cells and laminin dictate cholangiocytes’ fate in chronic liver disease
Abstract
Background and Aims In chronic liver diseases (CLD), when native hepatocytes enter replicative senescence, new hepatocytes are produced via differentiation of reactive cholangiocytes, also known as ductular reaction – DR - cells. However, this mechanism alone is insufficient to prevent liver failure, emphasizing the need for a deeper understanding to enhance its therapeutic potential. We hypothesize that signals driving DR differentiation into hepatocytes reside in the local niche, particularly extracellular matrix (ECM) composition and neighboring cells. Method We modeled CLD in mice using CCl 4 injections (3x/week for 6 weeks). Using Opn-iCreERT2; Rosa26RYFP mice, we tracked DR fate, and with Cdh5-iCreERT2; Rosa26RmT/mG mice, we studied LSEC origins. Mouse liver tissues were analyzed using immunohistochemistry (IHC), flow cytometry, RT-qPCR and RESOLVE molecular cartography for spatial transcriptomic. Double-spheroids were used to study ECM effect in vitro . We examined human liver tissues with double IHC and publicly available scRNA-seq datasets were used. Results We identified two populations of ductular reaction (DR) cells: those surrounded by laminin (Lam-DRs) and those without 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 laminin's role 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+ LSECs-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 chronic liver disease. Impact and implications Chronic liver disease progression is characterized by impaired hepatocyte regeneration, making alternative regenerative pathways such as DR–driven hepatocyte formation of particular interest. This study provides mechanistic insight into how the local microenvironment specifically capillarized CD34 + LSECs 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 DR-derived hepatocytes contribute modestly to overall parenchymal renewal, our results suggest that therapeutically modulating LSEC capillarization or ECM remodeling could represent a strategy to enhance regenerative competence in chronic liver disease, warranting further preclinical and translational investigation.
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BibTeX
@article{manco2026liver,
title = {{Liver sinusoidal endothelial cells and laminin dictate cholangiocytes’ fate in chronic liver disease}},
author = {Rita Manco and Camilla Moliterni and Elayne Neirynck and Rachel Claus and Maxime de Rudder and Corinne Picalausa and Leana Ducor and Montserrat Fraga and Laurent Coubeau and Alice Dongier and Pamela Baldin and Frédéric Lemaigre and Christine Sempoux and Alexandra Dili and Isabelle A Leclercq},
journal = {Journal of Hepatology},
year = {2026},
month = sep,
doi = {10.1016/j.jhep.2026.03.022},
url = {https://hal.science/hal-05749467v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Liver sinusoidal endothelial cells and laminin dictate cholangiocytes’ fate in chronic liver disease
AU - Rita Manco
AU - Camilla Moliterni
AU - Elayne Neirynck
AU - Rachel Claus
AU - Maxime de Rudder
AU - Corinne Picalausa
AU - Leana Ducor
AU - Montserrat Fraga
AU - Laurent Coubeau
AU - Alice Dongier
AU - Pamela Baldin
AU - Frédéric Lemaigre
AU - Christine Sempoux
AU - Alexandra Dili
AU - Isabelle A Leclercq
PY - 2026
DA - 2026/09/14
JO - Journal of Hepatology
DO - 10.1016/j.jhep.2026.03.022
UR - https://hal.science/hal-05749467v1
AB - Background and Aims In chronic liver diseases (CLD), when native hepatocytes enter replicative senescence, new hepatocytes are produced via differentiation of reactive cholangiocytes, also known as ductular reaction – DR - cells. However, this mechanism alone is insufficient to prevent liver failure, emphasizing the need for a deeper understanding to enhance its therapeutic potential. We hypothesize that signals driving DR differentiation into hepatocytes reside in the local niche, particularly extracellular matrix (ECM) composition and neighboring cells. Method We modeled CLD in mice using CCl 4 injections (3x/week for 6 weeks). Using Opn-iCreERT2; Rosa26RYFP mice, we tracked DR fate, and with Cdh5-iCreERT2; Rosa26RmT/mG mice, we studied LSEC origins. Mouse liver tissues were analyzed using immunohistochemistry (IHC), flow cytometry, RT-qPCR and RESOLVE molecular cartography for spatial transcriptomic. Double-spheroids were used to study ECM effect in vitro . We examined human liver tissues with double IHC and publicly available scRNA-seq datasets were used. Results We identified two populations of ductular reaction (DR) cells: those surrounded by laminin (Lam-DRs) and those without 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 laminin's role 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+ LSECs-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 chronic liver disease. Impact and implications Chronic liver disease progression is characterized by impaired hepatocyte regeneration, making alternative regenerative pathways such as DR–driven hepatocyte formation of particular interest. This study provides mechanistic insight into how the local microenvironment specifically capillarized CD34 + LSECs 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 DR-derived hepatocytes contribute modestly to overall parenchymal renewal, our results suggest that therapeutically modulating LSEC capillarization or ECM remodeling could represent a strategy to enhance regenerative competence in chronic liver disease, warranting further preclinical and translational investigation.
SN - 0168-8278
SN - 1600-0641
ER -