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Ectopic expression of murine CD47 minimizes macrophage rejection of human hepatocyte xenografts in immunodeficient mice

Authors

  • Johan M. Waern,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany
    3. Medical and Oncology Clinic, Södra Älvsborgs Sjukhus, Borås, Sweden
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  • Qinggong Yuan,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany
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  • Urda Rüdrich,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany
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  • Pablo D. Becker,

    1. Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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  • Kai Schulze,

    1. Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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  • Helene Strick-Marchand,

    1. Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM) U668, Paris, France
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  • Nicholas D. Huntington,

    1. Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM) U668, Paris, France
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  • Behrend J. Zacher,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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  • Karsten Wursthorn,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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  • James P. DiSanto,

    1. Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France
    2. Institut National de la Santé et de la Recherche Médicale (INSERM) U668, Paris, France
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  • Carlos A. Guzman,

    1. Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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  • Michael P. Manns,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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  • Michael Ott,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany
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    • Michael Bock

      Corresponding author
      1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
      2. Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany
      • Hepatic Cell Therapy, Cluster of Excellence REBIRTH, Dept. of Gastroenterology, Hepatology and Endocrinology, OE6810, Hannover Medical School, Carl-Neuberg-Str-1, 30625 Hannover, Germany
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      • These authors contributed equally to this work.

      • fax: +49 511 532 165122


    • Potential conflict of interest: Nothing to report.

    Abstract

    Macrophages play an important role in the rejection of xenogeneic cells and therefore represent a major obstacle to generating chimeric mice with human xenografts that are useful tools for basic and preclinical medical research. The signal inhibitory regulatory protein α (SIRPα) receptor is a negative regulator of macrophage phagocytic activity and interacts in a species-specific fashion with its ligand CD47. Furthermore, SIRPα polymorphism in laboratory mouse strains significantly affects the extent of human CD47-mediated toleration of human xenotransplants. Aiming to minimize macrophage activity and thus optimize human cell engraftment in immunodeficient mice, we lentivirally transduced murine CD47 (Cd47) into human liver cells. Human HepG2 liver cells expressing Cd47 were less frequently contacted and phagocytosed by murine RAW264.7 macrophages in vitro than their Cd47-negative counterparts. For the generation of human-mouse chimeric livers in immunodeficient BALB-ΔRAG/γc-uPA (urokinase-type plasminogen activator) mice, freshly thawed cryopreserved human hepatocytes were transduced with a lentiviral expression vector for Cd47 using a refined in vitro transduction protocol immediately before transplantation. In vivo, Cd47-positive human primary hepatocytes were selectively retained following engraftment in immunodeficient mice, leading to at least a doubling of liver repopulation efficiencies. Conclusion: We conclude that ectopic expression of murine Cd47 in human hepatocytes selectively favors engraftment upon transplantation into mice, a finding that should have a profound impact on the generation of robust humanized small animal models. Moreover, dominance of ectopically expressed murine Cd47 over endogenous human CD47 should also widen the spectrum of immunodeficient mouse strains suitable for humanization. (HEPATOLOGY 2012)

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