Gaucher iPSC-Derived Macrophages Produce Elevated Levels of Inflammatory Mediators and Serve as a New Platform for Therapeutic Development
Gaucher iPSC-Derived Macrophages Produce Elevated Levels of Inflammatory Mediators and Serve as a New Platform for Therapeutic Development
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DOI：
10.1002/stem.1732
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发表时间：
2014-09-01
期刊：
影响因子：
5.2
通讯作者：
Feldman, Ricardo A.
中科院分区：
文献类型：
--
作者：
Panicker, Leelamma M.;Miller, Diana;Feldman, Ricardo A.
戈谢病（GD）是由酸性β-葡糖脑苷脂酶（GCase; GBA）基因突变引起的常染色体隐性遗传疾病。GD的标志是存在脂质负载的戈谢巨噬细胞，其浸润骨髓和其他器官。这些病理性巨噬细胞被认为是GD患者血清中炎症介质水平升高的来源。由GD引起的免疫环境的改变被认为在GD患者中发生多发性骨髓瘤和其他恶性肿瘤的风险增加中起作用。为了直接确定戈谢巨噬细胞是否被异常激活以及它们的功能缺陷是否可以通过药理学干预逆转，我们通过来自1型、2型和3型GD患者的人诱导多能干细胞（hiPSC）的定向分化产生GD巨噬细胞。GD hiPSC衍生的巨噬细胞表达比对照细胞更高水平的肿瘤坏死因子α、IL-6和IL-1 β，并且该表型通过脂多糖处理而加剧。此外，GD hiPSC巨噬细胞在清除吞噬的红细胞方面表现出明显的延迟，重现了来自骨髓抽吸物的戈谢巨噬细胞中存在红细胞残留物。GD hiPSC巨噬细胞与重组GCase或与伴侣异法戈明和氨溴索孵育，在一定程度上纠正了GD巨噬细胞的异常表型，反映了其已知的临床疗效。我们得出结论，戈谢巨噬细胞是GD患者血清中炎症介质水平升高的可能来源，GD hiPSC是研究疾病机制和药物发现的有价值的新工具。
Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid beta-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 alpha, IL-6, and IL-1 beta 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.