Aberrant iPSC-derived human astrocytes in Alzheimer's disease
Aberrant iPSC-derived human astrocytes in Alzheimer's disease
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DOI：
10.1038/cddis.2017.89
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发表时间：
2017-03-01
影响因子：
9
通讯作者：
Mohamet, L.
中科院分区：
文献类型：
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作者：
Jones, V. C.;Atkinson-Dell, R.;Mohamet, L.
采用诱导多能干细胞（iPSC）技术，对阿尔茨海默病（AD）中人类星形胶质细胞的病理潜能进行了体外分析。在这里，我们报告了从健康个体和早发性家族性AD（FAD）或迟发性散发性AD（SAD）患者创建的人iPSC衍生的星形胶质细胞模型的开发。我们的化学定义和高效的模型提供了从皮质神经祖细胞（NPC）分化的30天内> 95%同质的人星形胶质细胞群体。所有星形胶质细胞表达的功能标志物包括胶质细胞酸性蛋白（GFAP）、兴奋性氨基酸转运蛋白1（EAAT 1）、S100 B和谷氨酰胺合成酶（GS），与体内成年星形胶质细胞相当。然而，来自SAD和FAD患者的诱导星形胶质细胞表现出明显的病理表型，具有明显不太复杂的形态学外观、总体萎缩特征和关键功能性星形胶质细胞标志物的异常定位。此外，来自相同患者的NPC没有显示出任何差异，因此，验证了重塑的星形胶质细胞不是有缺陷的神经中间体的结果。这项工作不仅为体外研究人类星形胶质细胞的机制提供了一个新的模型，而且为进一步探究AD早期星形胶质细胞自主事件以及识别治疗AD的新治疗靶点的可能性提供了理想的平台。
The pathological potential of human astroglia in Alzheimer's disease (AD) was analysed in vitro using induced pluripotent stem cell (iPSC) technology. Here, we report development of a human iPSC-derived astrocyte model created from healthy individuals and patients with either early-onset familial AD (FAD) or the late-onset sporadic form of AD (SAD). Our chemically defined and highly efficient model provides > 95% homogeneous populations of human astrocytes within 30 days of differentiation from cortical neural progenitor cells (NPCs). All astrocytes expressed functional markers including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-1 (EAAT1), S100B and glutamine synthetase (GS) comparable to that of adult astrocytes in vivo. However, induced astrocytes derived from both SAD and FAD patients exhibit a pronounced pathological phenotype, with a significantly less complex morphological appearance, overall atrophic profiles and abnormal localisation of key functional astroglial markers. Furthermore, NPCs derived from identical patients did not show any differences, therefore, validating that remodelled astroglia are not as a result of defective neural intermediates. This work not only presents a novel model to study the mechanisms of human astrocytes in vitro, but also provides an ideal platform for further interrogation of early astroglial cell autonomous events in AD and the possibility of identification of novel therapeutic targets for the treatment of AD.