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Am J Pathol. 2015 Aug;185(8):2194-205. doi: 10.1016/j.ajpath.2015.04.021. Epub 2015 Jun 19.

WNT5A inhibits hepatocyte proliferation and concludes β-catenin signaling in liver regeneration.

Author information

1
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
2
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Ri.MED Foundation, Palermo, Italy; Institute of Biomedicine and Molecular Immunology Alberto Monroy, National Research Council, Palermo, Italy.
3
Ri.MED Foundation, Palermo, Italy; Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
4
Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
5
Visual Systems Group, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
6
Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, NIH, Frederick, Maryland.
7
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Electronic address: smonga@pitt.edu.

Abstract

Activation of Wnt/β-catenin signaling during liver regeneration (LR) after partial hepatectomy (PH) is observed in several species. However, how this pathway is turned off when hepatocyte proliferation is no longer required is unknown. We assessed LR in liver-specific knockouts of Wntless (Wls-LKO), a protein required for Wnt secretion from a cell. When subjected to PH, Wls-LKO showed prolongation of hepatocyte proliferation for up to 4 days compared with littermate controls. This coincided with increased β-catenin-T-cell factor 4 interaction and cyclin-D1 expression. Wls-LKO showed decreased expression and secretion of inhibitory Wnt5a during LR. Wnt5a expression increased between 24 and 48 hours, and Frizzled-2 between 24 and 72 hours, after PH in normal mice. Treatment of primary mouse hepatocytes and liver tumor cells with Wnt5a led to a notable decrease in β-catenin-T-cell factor activity, cyclin-D1 expression, and cell proliferation. Intriguingly, Wnt5a-LKO did not display any prolongation of LR because of compensation by other cells. In addition, Wnt5a-LKO hepatocytes failed to respond to exogenous Wnt5a treatment in culture because of a compensatory decrease in Frizzled-2 expression. In conclusion, we demonstrate Wnt5a to be, by default, a negative regulator of β-catenin signaling and hepatocyte proliferation, both in vitro and in vivo. We also provide evidence that the Wnt5a/Frizzled-2 axis suppresses β-catenin signaling in hepatocytes in an autocrine manner, thereby contributing to timely conclusion of the LR process.

PMID:
26100214
PMCID:
PMC4530131
DOI:
10.1016/j.ajpath.2015.04.021
[Indexed for MEDLINE]
Free PMC Article

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