Lineage fate of ductular reactions in liver injury and carcinogenesis

Ductular reactions (DRs) are observed in virtually all forms of human liver disease. Nevertheless, the histogenesis and function of DRs in liver injury are not entirely understood. It is widely believed that DRs contain bipotential liver progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both, cholangiocytes and hepatocytes, and may eventually give rise to hepatocellular carcinoma (HCC). Here we provide a thorough analysis on the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. Using a mouse model that allows highly efficient and specific lineage labeling of the biliary compartment, we demonstrate that biliary cells are the predominant precursors of DRs found in multiple experimental and genetic liver injury models but lack significant capacity to produce new hepatocytes, even during prolonged liver injuries up to 12 months. Genetic modulation of Notch and/or Wnt/β-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to deliberate DRs from their biliary fate towards the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. Our findings question the presence of an adult LPC compartment within biliary-derived DRs that physiologically functions to replenish hepatocytes or give rise to HCCs.

Corresponding author: Geisler, Fabian

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