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Cited by 92Lysosomal Storage Disorders ResearchGlycogen Storage Diseases and MyoclonusSphingolipid Metabolism and Signaling

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

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Panicker, Leelamma M., Miller, Diana, Awad, Ola, Bose, Vivek, Lun, Yu, Park, Tea Soon, Zambidis, Elias T., Sgambato, Judi A. +1 more·2014·Stem Cells
DOI 10.1002/stem.1732PMC PMC4138241
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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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  • GBA deficiency increases proinflammatory cytokine expression in iPSC-derived macrophages.

    “In vitro study using an iPSCs derived macrophage revealed that GBA deficiency increased proinflammatory cytokine expression.262,263”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [263]

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Authors
Panicker, L. M., Miller, D., Awad, O., Bose, V., Lun, Y., Park, T. S., Zambidis, E. T., Sgambato, J. A., & Feldman, R. A.
Affiliations
  • University of Maryland, Baltimore (US)
  • Johns Hopkins University (US)
Corresponding author
Feldman, Ricardo A.
ORCID
Venue
Stem Cells
Publisher
Oxford University Press (OUP)
Published
2014-08-18
Volume
32
Issue
9
Pages
2338-2349
ISSN
  • 1066-5099 (ISSN-L)
  • 1549-4918
DOI
10.1002/stem.1732
PMC
PMC4138241
OpenAlex
W1520064365
Cited by
92
References
4
Citations by year
2026: 4 · 2025: 4 · 2024: 8 · 2023: 9 · 2022: 9 · 2021: 7 · 2020: 10 · 2019: 5 · 2018: 4 · 2017: 10 · 2016: 11 · 2015: 11
FWCI
7.11
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Stem Cells (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • March of Dimes Foundation (6-FY10-334)
  • Maryland Stem Cell Research Fund (2009-MSCRFII-0082-00, 2007-MSCRFE-0110-00, 2011-MSCRF-II-0008-00, 2007-MSCRF II-0379-00)
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R03HL096220, U01HL099775)
  • National Eye Institute (R01EY023962)
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
Keywords
Gaucher disease, induced pluripotent stem cells, macrophage differentiation, GBA mutations, inflammatory mediators, TNF-α, interleukin-6, IL-1β, lipopolysaccharide, phagocytosis, isofagomine, ambroxol, disease modeling, drug discovery
MeSH terms
Animals, Cell Differentiation, Female, Gaucher Disease, Humans, Macrophages, Male, Cytokines, Mice, SCID, Mice, Inbred NOD, Mice, Induced Pluripotent Stem Cells

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