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Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18384-9. doi: 10.1073/pnas.1116386108. Epub 2011 Oct 31.

Depletion of β-catenin from mature hepatocytes of mice promotes expansion of hepatic progenitor cells and tumor development.

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1
Department of Microbiology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.

Abstract

Depletion of β-catenin impairs regeneration of the rapid turn-over gut epithelial cells, but appears dispensable for that of the slow turn-over mature hepatocytes in mice until 1 y of age. As the life span of mature murine hepatocytes is about 400 d, we studied conditional β-catenin knockout mice (Alb-Cre;Ctnnb1(flx/flx)) until 20 mo of age to determine the function of β-catenin in the postnatal liver. β-catenin was absent from the hepatocytes of β-catenin knockout mice 4 wk after delivery. From 9 mo of age, hepatocytes were gradually replaced by newly formed β-catenin-positive hepatocytes, which constituted about 90% of hepatocytes at 18-20 mo of age. This process was accompanied by active proliferation of bile duct/ductule cells. β-catenin-positive hepatocytes exhibited elevated proliferation activity and expression of progenitor cell markers, but lower albumin and Cre. This might explain their intact β-catenin protein, and suggest their origins from hepatic progenitor cells. Liver tumors arose spontaneously from β-catenin-positive cells, and tumorigenesis was accelerated by hepatitis B X protein. These results indicate β-catenin critical for the regeneration of mature hepatocytes. Failure to regenerate mature hepatocytes results in proliferation of hepatic progenitor cells that are able to maintain liver function but are predisposed to form liver tumors.

PMID:
22042854
PMCID:
PMC3215019
DOI:
10.1073/pnas.1116386108
[Indexed for MEDLINE]
Free PMC Article
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