Liver-specific ablation of integrin-linked kinase in mice results in abnormal histology, enhanced cell proliferation, and hepatomegaly

Authors

  • Vasiliki Gkretsi,

    1. Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
    Current affiliation:
    1. Institute of Immunology, Biomedical Sciences Research Centre “Alexander Fleming”, Vari, Greece
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  • Udayan Apte,

    1. Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Wendy M. Mars,

    1. Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • William C. Bowen,

    1. Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Jian-Hua Luo,

    1. Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Yu Yang,

    1. Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Yan P. Yu,

    1. Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Ann Orr,

    1. Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • René St.-Arnaud,

    1. Shriners Hospital and McGill University, Montréal, Québec, Canada
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  • Shoukat Dedhar,

    1. British Columbia Cancer Agency and Vancouver Hospital, Jack Bell Research Center, Vancouver, British Columbia, Canada
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  • Klaus H. Kaestner,

    1. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA
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  • Chuanyue Wu,

    1. Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • George K. Michalopoulos

    Corresponding author
    1. Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
    • Department of Pathology, University of Pittsburgh School of Medicine, S-410 Biomedical Science Tower, Pittsburgh, PA 15261
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    • fax: 412-648-9846


  • Potential conflict of interest: Nothing to report.

Abstract

Hepatocyte differentiation and proliferation are greatly affected by extracellular matrix (ECM). Primary hepatocytes cultured without matrix dedifferentiate over time, but matrix overlay quickly restores differentiation. ECM also is critical in liver regeneration where ECM degradation and reconstitution are steps in the regenerative process. Integrin-linked kinase (ILK) is a cell-ECM-adhesion component implicated in cell–ECM signaling by means of integrins. We investigated the role of ILK in whole liver by using the LoxP/Cre model system. ILK was eliminated from the liver by mating homozygous ILK-floxed animals with mice expressing Cre-recombinase under control of the α fetoprotein enhancer and albumin promoter. After ablation of ILK, animals are born normal. Soon after birth, however, they develop histologic abnormalities characterized by disorderly hepatic plates, increased proliferation of hepatocytes and biliary cells, and increased deposition of extracellular matrix. Cell proliferation is accompanied by increased cytoplasmic and nuclear stabilization of β-catenin. After this transient proliferation of all epithelial components, proliferation subsides and final liver to body weight ratio in livers with ILK deficient hepatocytes is two times that of wild type. Microarray analysis of gene expression during the stage of cell proliferation shows up-regulation of integrin and matrix-related genes and a concurrent down-regulation of differentiation-related genes. After the proliferative stage, however, the previous trends are reversed resulting in a super-differentiated phenotype in the ILK-deficient livers. Conclusion: Our results show for the first time in vivo the significance of ILK and hepatic ECM-signaling for regulation of hepatocyte proliferation and differentiation. (HEPATOLOGY 2008;48:1932-1941.)

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