Liver Sinusoidal Endothelial Cells and Laminin dictate cholangiocytes’ fate in chronic liver disease

In chronic liver disease (CLD), hepatocyte senescence limits conventional regeneration, prompting an alternative regeneration mechanism through transdifferentiation of reactive cholangiocytes (or ductular reaction cells - DRs). Yet, this alone is insufficient to avoid liver failure and transplantation, highlighting the importance of a deeper understanding of the mechanism. We focused on the DRs microenvironment. We identified laminin as a crucial component of the extracellular matrix to maintain DRs in a biliary phenotype, preventing their differentiation into hepatocytes. Liver sinusoidal endothelial cells (LSEC) are the cells regulating laminin degradation around DRs. By preventing LSEC capillarization during CLD, we enhanced DR differentiation into hepatocytes. We also demonstrated this causality in human samples. This is the first time that a mechanism for DR-driven regeneration has been described.