Lineage fate of ductular reactions in liver injury and carcinogenesis
Autor: | Mathias Heikenwalder, Maike Sander, Jorge Ferrer, Fabian Geisler, S Dürl, Julian Thalhammer, Petia Jeliazkova, Roland M. Schmid, S Jörs, Marc Ringelhan, Jens T. Siveke |
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Rok vydání: | 2015 |
Předmět: |
Male
Pathology Histogenesis Research & Experimental Medicine medicine.disease_cause Gastroenterology Mice Liver Neoplasms Experimental HEPATOCELLULAR-CARCINOMA Wnt Signaling Pathway Liver injury Stem Cells Wnt signaling pathway General Medicine 11 Medical And Health Sciences Liver regeneration medicine.anatomical_structure Medicine Research & Experimental Liver Hepatocyte MOUSE-LIVER OVAL CELLS Stem cell Life Sciences & Biomedicine STEM-CELLS Research Article medicine.medical_specialty ADULT HEPATOCYTES Carcinoma Hepatocellular Immunology Mice Transgenic Biology behavioral disciplines and activities MATURE HEPATOCYTES Internal medicine mental disorders medicine Animals Humans Progenitor cell HEPATIC PROGENITOR CELLS Science & Technology IN-VITRO HCCS medicine.disease eye diseases BILIARY EPITHELIAL-CELLS Cancer research Hepatocytes Bile Ducts Carcinogenesis |
Zdroj: | J. Clin. Invest. 125, 2445-2457 (2015) |
Popis: | 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. |
Databáze: | OpenAIRE |
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