[HTML][HTML] Lineage fate of ductular reactions in liver injury and carcinogenesis

S Jörs, P Jeliazkova, M Ringelhan… - The Journal of …, 2015 - Am Soc Clin Investig
S Jörs, P Jeliazkova, M Ringelhan, J Thalhammer, S Dürl, J Ferrer, M Sander
The Journal of clinical investigation, 2015Am Soc Clin Investig
Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however,
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 used a murine model that allows
highly efficient and specific lineage labeling of the biliary compartment to analyze the …
Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however, 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 used a murine model that allows highly efficient and specific lineage labeling of the biliary compartment to analyze the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. In multiple experimental and genetic liver injury models, biliary cells were the predominant precursors of DRs but lacked substantial capacity to produce new hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic modulation of NOTCH and/or WNT/β-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to redirect DRs from biliary differentiation toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. In summary, we found no evidence in our system to support mouse biliary-derived DRs as an LPC pool to replenish hepatocytes in a quantitatively relevant way in injury or evidence that DRs give rise to HCCs.
The Journal of Clinical Investigation