title: Gaucher iPSC-derived macrophages produce elevated levels of inflammatory mediators and serve as a new platform for therapeutic development.
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.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Leelamma M
authors.initials: LM
authors.lastname: Panicker
authors.forename: Diana
authors.initials: D
authors.lastname: Miller
authors.forename: Ola
authors.initials: O
authors.lastname: Awad
authors.forename: Vivek
authors.initials: V
authors.lastname: Bose
authors.forename: Yu
authors.initials: Y
authors.lastname: Lun
authors.forename: Tea Soon
authors.initials: TS
authors.lastname: Park
authors.forename: Elias T
authors.initials: ET
authors.lastname: Zambidis
authors.forename: Judi A
authors.initials: JA
authors.lastname: Sgambato
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Feldman
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D005776:Gaucher Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID
chemical_list: D016207:Cytokines
keywords: Cell biology; Experimental models; Induced pluripotent stem cells; Monocyte; Reprogramming