Neural stem cells for disease modeling of Wolman disease and evaluation of therapeutics.
Neural stem cells for disease modeling of Wolman disease and evaluation of therapeutics.
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DOI：
10.1186/s13023-017-0670-9
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发表时间：
2017-06-28
影响因子：
3.7
通讯作者：
Zheng W
中科院分区：
文献类型：
--
作者：
Aguisanda F;Yeh CD;Chen CZ;Li R;Beers J;Zou J;Thorne N;Zheng W
沃尔曼病 (WD) 是一种罕见的溶酶体贮积症，由编码溶酶体酸性脂肪酶 (LAL) 的 LIPA 基因突变引起。 LAL 功能缺陷会导致胆固醇酯和甘油三酯在溶酶体中积聚。死亡通常发生在生命的第一年内。虽然最近出现了酶替代疗法，但目前还没有针对 WD 的小分子药物治疗。我们从两个 WD 患者真皮成纤维细胞系中产生了诱导多能干细胞 (iPSC)，随后将它们分化为神经干细胞 (NSC)。 WD NSC 表现出中性脂质积累、严重缺乏 LAL 活性和 LysoTracker 染料染色增加的标志性疾病表型。酶替代治疗显着降低了这些细胞的 WD 表型。此外，δ-生育酚（DT）和羟丙基-β-环糊精（HPBCD）显着减小了WD NSC中的溶酶体大小，并且在DT/HPBCD联合治疗中观察到增强的效果。结果表明，这些 WD NSC 是有效的基于细胞的疾病模型，具有特征性的疾病表型，可用于评估药物疗效和筛选化合物。 DT 和 HPBCD 均可减少 WD 细胞中的 LysoTracker 染料染色。这些细胞可用于进一步剖析 WD 的病理学、评估化合物功效，并作为高通量药物筛选的平台，以鉴定用于治疗开发的新化合物。本文的在线版本 (doi:10.1186/s13023-017-0670-9) 包含补充材料，可供授权用户使用。
Wolman disease (WD) is a rare lysosomal storage disorder that is caused by mutations in the LIPA gene encoding lysosomal acid lipase (LAL). Deficiency in LAL function causes accumulation of cholesteryl esters and triglycerides in lysosomes. Fatality usually occurs within the first year of life. While an enzyme replacement therapy has recently become available, there is currently no small-molecule drug treatment for WD. We have generated induced pluripotent stem cells (iPSCs) from two WD patient dermal fibroblast lines and subsequently differentiated them into neural stem cells (NSCs). The WD NSCs exhibited the hallmark disease phenotypes of neutral lipid accumulation, severely deficient LAL activity, and increased LysoTracker dye staining. Enzyme replacement treatment dramatically reduced the WD phenotype in these cells. In addition, δ-tocopherol (DT) and hydroxypropyl-beta-cyclodextrin (HPBCD) significantly reduced lysosomal size in WD NSCs, and an enhanced effect was observed in DT/HPBCD combination therapy. The results demonstrate that these WD NSCs are valid cell-based disease models with characteristic disease phenotypes that can be used to evaluate drug efficacy and screen compounds. DT and HPBCD both reduce LysoTracker dye staining in WD cells. The cells may be used to further dissect the pathology of WD, evaluate compound efficacy, and serve as a platform for high-throughput drug screening to identify new compounds for therapeutic development. The online version of this article (doi:10.1186/s13023-017-0670-9) contains supplementary material, which is available to authorized users.