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
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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