Repopulation of mouse liver with human hepatocytes and in vivo infection with hepatitis B virus

Authors

  • Maura Dandri,

    1. Heinrich-Pette-Institut for Experimental Virology and Immunology, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany
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  • Martin R. Burda,

    1. Heinrich-Pette-Institut for Experimental Virology and Immunology, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany
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  • Eva Török,

    1. Department of Hepatobiliary Surgery and Transplantation, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany
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  • Joerg M. Pollok,

    1. Department of Hepatobiliary Surgery and Transplantation, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany
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  • Alicja Iwanska,

    1. Heinrich-Pette-Institut for Experimental Virology and Immunology, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany
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  • Gunhild Sommer,

    1. Heinrich-Pette-Institut for Experimental Virology and Immunology, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany
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  • Xavier Rogiers,

    1. Department of Hepatobiliary Surgery and Transplantation, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany
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  • Charles E. Rogler,

    1. Albert Einstein College of Medicine, Marion Bessin Liver Research Center, Bronx, NY
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  • Sanjeev Gupta,

    1. Albert Einstein College of Medicine, Marion Bessin Liver Research Center, Bronx, NY
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  • Hans Will,

    1. Heinrich-Pette-Institut for Experimental Virology and Immunology, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany
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  • Heiner Greten,

    1. Department of Medicine, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany
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  • Joerg Petersen M.D.

    Corresponding author
    1. Heinrich-Pette-Institut for Experimental Virology and Immunology, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany
    2. Department of Medicine, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany
    • Klinik und Poliklinik für Innere Medizin Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. E-mail: petersen@hpi.uni-hamburg.de; fax: (49) 40-42803-8065.
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Abstract

Mice containing livers repopulated with human hepatocytes would provide excellent in vivo models for studies on human liver diseases and hepatotropic viruses, for which no permissive cell lines exist. Here, we report partial repopulation of the liver of immunodeficient urokinase-type plasminogen activator (uPA)/recombinant activation gene-2 (RAG-2) mice with normal human hepatocytes isolated from the adult liver. In the transplanted mice, the production of human albumin was demonstrated, indicating that human hepatocytes remained functional in the mouse liver for at least 2 months after transplantation. Inoculation of transplanted mice with human hepatitis B virus (HBV) led to the establishment of productive HBV infection. According to human-specific genomic DNA analysis and immunostaining of cryostat liver sections, human hepatocytes were estimated to constitute up to 15% of the uPA/RAG-2 mouse liver. This is proof that normal human hepatocytes can integrate into the mouse hepatic parenchyma, undergo multiple cell divisions, and remain permissive for a human hepatotropic virus in a xenogenic liver. This system will provide new opportunities for studies on etiology and therapy of viral and nonviral human liver diseases, as well as on hepatocyte biology and hepatocellular transplantation. (HEPATOLOGY 2001;33:981-988.)

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