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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Induced pluripotent stem cell model recapitulatespathologic hallmarks of Gaucher disease
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Induced pluripotent stem cell model recapitulatespathologic hallmarks of Gaucher disease

机译：诱导的多能干细胞模型概括了高雪氏病的病理学特征

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摘要

Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid p-glucocerebrosidase gene. To model GD, we generated human induced pluripotent stem cells (hiPSC), by reprog-ramming skin fibroblasts from patients with type 1 (N370S/N370S), type 2 (L444P/RecNcil), and type 3 (L444P/L444P) GD. Pluripotency was demonstrated by the ability of GD hiPSC to differentiate to all three germ layers and to form teratomas in vivo. GD hiPSC differentiated efficiently to the cell types most affected in GD, i.e., macro-phages and neuronal cells. GD hiPSC-macrophages expressed macrophage-specific markers, were phagocytic, and were capable of releasing inflammatory mediators in response to LPS. Moreover, GD hiPSC-macrophages recapitulated the phenotypic hallmarks of the disease. They exhibited low glucocerebrosidase (GC) enzymatic activity and accumulated sphingolipids, and their lysosomal functions were severely compromised. GD hiPSC-macrophages had a defect in their ability to clear phagocytosed RBC, a phenotype of tissue-infiltrating GD macrophages. The kinetics of RBC clearance by types 1, 2, and 3 GD hiPSC-macrophages correlated with the severity of the mutations. Incubation with recombinant GC completely reversed the delay in RBC clearance from all three types of GD hiPSC-macrophages, indicating that their functional defects were indeed caused by GC deficiency. However, treatment of induced macrophages with the chaperone isofagomine restored phagocytosed RBC clearance only partially, regardless of genotype. These findings are consistent with the known clinical efficacies of recombinant GC and isofagomine. We conclude that cell types derived from GD hiPSC can effectively recapitulate pathologic hallmarks of the disease.
机译：高雪氏病（GD）是由酸性p-葡萄糖脑苷脂酶基因突变引起的常染色体隐性遗传疾病。为了对GD进行建模，我们通过对1型（N370S / N370S），2型（L444P / RecNcil）和3型（L444P / L444P）GD患者的皮肤成纤维细胞进行重组改造来生成人诱导的多能干细胞（hiPSC）。 GD hiPSC能够分化为所有三个细菌层并在体内形成畸胎瘤的能力证明了其多能性。 GD hiPSC有效分化为受GD影响最大的细胞类型，即巨噬细胞和神经元细胞。 GD hiPSC巨噬细胞表达巨噬细胞特异性标记，具有吞噬作用，并能够响应LPS释放炎性介质。此外，GD hiPSC巨噬细胞概括了该疾病的表型特征。他们表现出低葡糖脑苷脂酶（GC）的酶活性和积累的鞘脂，其溶酶体功能受到严重损害。 GD hiPSC巨噬细胞清除吞噬的RBC（一种组织浸润性GD巨噬细胞的表型）的能力存在缺陷。 1、2和3型GD hiPSC巨噬细胞清除RBC的动力学与突变的严重程度相关。重组GC孵育完全逆转了所有三种GD hiPSC巨噬细胞对RBC清除的延迟，表明它们的功能缺陷确实是由GC缺乏引起的。然而，无论基因型如何，用伴侣异黄酮伴侣治疗诱导的巨噬细胞只能部分恢复吞噬的RBC清除率。这些发现与重组GC和异黄酮的已知临床疗效一致。我们得出的结论是，源自GD hiPSC的细胞类型可以有效地概括该疾病的病理特征。

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    Leelamma M. Panicked; Diana Miller; Tea Soon Park; Brijesh Patel; Judi L. Azevedo; Ola Awad; M. Athar Masood; Timothy D. Veenstra; Ehud Goldin; Barbara K. Stubblefield; Nahid Tayebi; Swamy K. Polumuri; Stefanie N. Vogel; Ellen Sidransky; Elias T. Zambidis; Ricardo A. Feldman;

  • 作者单位

    Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201;

    Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201;

    institute for Cell Engineering SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702,Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University School of Medicine, Baltimore, MD 21205 SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702;

    Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201;

    Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201;

    Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201;

    Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702;

    Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702;

    Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;

    Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;

    Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;

    Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201;

    Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201;

    Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;

    institute for Cell Engineering SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702,Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University School of Medicine, Baltimore, MD 21205 SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702;

    Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    gaucher model; gaucher macrophages; lipid storage disease; glucosylsphingolipids; erythrophagocytosis;

    机译：高雪模型高雪巨噬细胞脂质贮积病;糖基鞘糖脂;红细胞吞噬作用;

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