The liver has a remarkable capacity for repair and regeneration following injury. In human disease, hepatic damage induces ductular reactions (DRs), which are thought to be the source of the liver progentitor cells (LPCs) that restore cholangiocyte and hepatocyte populations. Ductular reactive cells (DRCs) typically arise from the biliary compartment; however, there is evidence that some DRCs are of hepatocyte origin in certain liver injury models. Simone Jörs, Petia Jeliazkova, and colleagues at Technische Universität München developed a murine model that allows specific labeling and tracing of biliary cells to evaluate the origin of DRs and LPCs in response to a variety of hepatic injuries. While in the majority of liver injury models, biliary cells were the primary source of DRs, this population lacked capacity to produce new hepatocytes, even in response to prolonged injury. NOTCH and WNT/β-catenin signaling have been proposed to drive DRC differentiation toward a biliary or hepatocyte phenotype. Loss of NOTCH or activation of WNT/β-catenin in biliary cells reduced DR initiation and expansion; however, these DRs were not directed toward a hepatocyte linage. Moreover, DRs did not give rise to tumors in models of hepatocellular carcinoma (HCC). Together, the results of this study indicate that biliary-derived DRs are not a source of LPCs in the regenerating liver and do not give rise to HCC. The accompanying images show sections of the liver from mice on a choline-deficient ethionine-supplemented [CDE] diet, which induces hepatocellular injury, for 4 months. The image on the left is a low magnification of the expansion of biliary-derived (red) DRs (CK19, green) in response to CDE. The image on the right demonstrates that only a very small fraction of the biliary-derived cells (red) also express the hepatocyte marker HNF4α (green), an observation that was not readily seen in other models.
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.
Simone Jörs, Petia Jeliazkova, Marc Ringelhan, Julian Thalhammer, Stephanie Dürl, Jorge Ferrer, Maike Sander, Mathias Heikenwalder, Roland M. Schmid, Jens T. Siveke, Fabian Geisler