Gaucher iPSC-Derived Macrophages Produce Elevated Levels of Inflammatory Mediators and Serve as a New Platform for Therapeutic Development

Authors

  • Leelamma M. Panicker,

    1. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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  • Diana Miller,

    1. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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  • Ola Awad,

    1. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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  • Vivek Bose,

    1. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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  • Yu Lun,

    1. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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  • Tea Soon Park,

    1. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
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  • Elias T. Zambidis,

    1. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
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  • Judi A. Sgambato,

    1. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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  • Ricardo A. Feldman

    Corresponding author
    1. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
    • Correspondence: Ricardo A. Feldman, Ph.D., Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, HSF-1, Room 380, Baltimore, Maryland 21201, Telephone: 410-706-4198; Fax: 410-706-2129; e-mail: rfeldman@umaryland.edu

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Abstract

Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid β-glucocerebrosidase (GCase; GBA) gene. The hallmark of GD is the presence of lipid-laden Gaucher macrophages, which infiltrate bone marrow and other organs. These pathological macrophages are believed to be the sources of elevated levels of inflammatory mediators present in the serum of GD patients. The alteration in the immune environment caused by GD is believed to play a role in the increased risk of developing multiple myeloma and other malignancies in GD patients. To determine directly whether Gaucher macrophages are abnormally activated and whether their functional defects can be reversed by pharmacological intervention, we generated GD macrophages by directed differentiation of human induced pluripotent stem cells (hiPSC) derived from patients with types 1, 2, and 3 GD. GD hiPSC-derived macrophages expressed higher levels of tumor necrosis factor α, IL-6, and IL-1β than control cells, and this phenotype was exacerbated by treatment with lipopolysaccharide. In addition, GD hiPSC macrophages exhibited a striking delay in clearance of phagocytosed red blood cells, recapitulating the presence of red blood cell remnants in Gaucher macrophages from bone marrow aspirates. Incubation of GD hiPSC macrophages with recombinant GCase, or with the chaperones isofagomine and ambroxol, corrected the abnormal phenotypes of GD macrophages to an extent that reflected their known clinical efficacies. We conclude that Gaucher macrophages are the likely source of the elevated levels of inflammatory mediators in the serum of GD patients and that GD hiPSC are valuable new tools for studying disease mechanisms and drug discovery. Stem Cells 2014;32:2338–2349

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