National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA; Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
Exp Cell Res. 2022 Mar 1;412(1):113007. doi: 10.1016/j.yexcr.2021.113007. Epub 2022 Jan 4.
Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a rare, lysosomal disorder caused by mutations in a gene encoding iduronate-2-sulfatase (IDS). IDS deficiency results in an accumulation of glycosaminoglycans (GAGs) and secondary accumulations of other lipids in lysosomes. Symptoms of MPS II include a variety of soft and hard tissue problems, developmental delay, and deterioration of multiple organs. Enzyme replacement therapy is an approved treatment for MPS II, but fails to improve neuronal symptoms. Cell-based neuronal models of MPS II disease are needed for compound screening and drug development for the treatment of the neuronal symptoms in MPS II. In this study, three induced pluripotent stem cell (iPSC) lines were generated from three MPS II patient-derived dermal fibroblast cell lines that were differentiated into neural stem cells and neurons. The disease phenotypes were measured using immunofluorescence staining and Nile red dye staining. In addition, the therapeutic effects of recombinant human IDS enzyme, delta-tocopherol (DT), and hydroxypropyl-beta-cyclodextrin (HPBCD) were determined in the MPS II disease cells. Finally, the neural stem cells from two of the MPS II iPSC lines exhibited typical disease features including a deficiency of IDS activity, abnormal glycosaminoglycan storage, and secondary lipid accumulation. Enzyme replacement therapy partially rescued the disease phenotypes in these cells. DT showed a significant effect in reducing the secondary accumulation of lipids in the MPS II neural stem cells. In contrast, HPBCD displayed limited or no effect in these cells. Our data indicate that these MPS II cells can be used as a cell-based disease model to study disease pathogenesis, evaluate drug efficacy, and screen compounds for drug development.
黏多糖贮积症 II 型（MPS II），又称亨特综合征，是一种罕见的溶酶体贮积病，由编码艾杜糖-2-硫酸酯酶（IDS）的基因突变引起。IDS 缺乏导致糖胺聚糖（GAGs）和其他脂质在溶酶体中的继发性积累。MPS II 的症状包括各种软组织和硬组织问题、发育迟缓以及多个器官的恶化。酶替代疗法是一种已批准的 MPS II 治疗方法，但不能改善神经元症状。需要基于细胞的 MPS II 疾病神经元模型来进行化合物筛选和药物开发，以治疗 MPS II 中的神经元症状。在这项研究中，从三个 MPS II 患者来源的皮肤成纤维细胞系生成了三个诱导多能干细胞（iPSC）系，并将其分化为神经干细胞和神经元。使用免疫荧光染色和尼罗红染料染色来测量疾病表型。此外，还在 MPS II 疾病细胞中测定了重组人 IDS 酶、δ-生育酚（DT）和羟丙基-β-环糊精（HPBCD）的治疗效果。最后，来自两个 MPS II iPSC 系的神经干细胞表现出典型的疾病特征，包括 IDS 活性缺乏、异常糖胺聚糖储存和继发性脂质积累。酶替代疗法部分挽救了这些细胞的疾病表型。DT 在减少 MPS II 神经干细胞中脂质的继发性积累方面显示出显著效果。相比之下，HPBCD 在这些细胞中显示出有限或没有效果。我们的数据表明，这些 MPS II 细胞可用作基于细胞的疾病模型来研究疾病发病机制、评估药物疗效和筛选药物开发的化合物。
