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Lineage fate of ductular reactions in liver injury and carcinogenesis

Item Type:Article
Title:Lineage fate of ductular reactions in liver injury and carcinogenesis
Creators Name:Jörs, S. and Jeliazkova, P. and Ringelhan, M. and Thalhammer, J. and Dürl, S. and Ferrer, J. and Sander, M. and Heikenwalder, M. and Schmid, R.M. and Siveke, J.T. and Geisler, F.
Abstract: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.
Keywords:Bile Ducts, Hepatocellular Carcinoma, Hepatocytes, Liver, Experimental Liver Neoplasms, Stem Cells, Wnt Signaling Pathway, Transgenic Mice, Animals, Mice
Source:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
Page Range:2445-57
Date:1 June 2015
Official Publication:https://doi.org/10.1172/jci78585
PubMed:View item in PubMed

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