Characterization of cellular phenotypes in neurons derived from induced pluripotent stem cells of male patients with Fabry disease
Characterization of cellular phenotypes in neurons derived from induced pluripotent stem cells of male patients with Fabry disease
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DOI：
10.1002/jimd.12567
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发表时间：
2022-11-03
影响因子：
4.2
通讯作者：
Eto，Yoshikatsu
中科院分区：
文献类型：
--
作者：
Miyajima，Takashi;Saito，Ryo;Eto，Yoshikatsu
法布里病（FD）是一种X连锁的遗传性溶酶体代谢紊乱，由α -半乳糖苷酶a缺乏引起的globotriaosyl神经酰胺（Gb3）在各器官中积累。FD的临床特征包括肾脏、心脏和周围神经系统的进行性损害。此外，FD患者常出现抑郁、痴呆等神经精神症状，这些症状被认为是由于Gb3积聚导致脑血管及部分神经元细胞损伤所致。虽然对FD患者尸检脑组织的分析显示没有Gb3的积累，但在包括海马在内的几个脑区域的神经元中发现了Gb3的异常沉积。因此，在本研究中，我们从FD患者身上获得诱导多能干细胞（induced pluripotent stem cells, iPSCs），并将其分化为神经元细胞，研究FD神经元的病理和生物学变化。神经干细胞（NSCs）和神经元从我们生成的iPSCs中成功分化；但未见细胞损伤和形态学改变。免疫染色显示NSCs和神经元中未见Gb3积累。透射电镜未发现任何斑马体样结构或包涵体，这是FD的特征。这些结果表明，FD - iPSCs衍生的神经细胞形态正常，没有Gb3积累。iPSC衍生的神经元可能需要更多的体内环境样培养来复制疾病特异性特征。
Fabry disease (FD) is an X‐linked inherited lysosomal metabolism disorder in which globotriaosylceramide (Gb3) accumulates in various organs resulting from a deficiency in alpha‐galactosidase A. The clinical features of FD include progressive impairments of the renal, cardiac, and peripheral nervous systems. In addition, patients with FD often develop neuropsychiatric symptoms, such as depression and dementia, which are believed to be induced by the cellular injury of cerebrovascular and partially neuronal cells due to Gb3 accumulation. Although the analysis of autopsy brain tissue from patients with FD showed no accumulation of Gb3, abnormal deposits of Gb3 were found in the neurons of several brain areas, including the hippocampus. Therefore, in this study, we generated induced pluripotent stem cells (iPSCs) from patients with FD and differentiated them into neuronal cells to investigate pathological and biological changes in the neurons of FD. Neural stem cells (NSCs) and neurons were successfully differentiated from the iPSCs we generated; however, cellular damage and morphological changes were not found in these cells. Immunostaining revealed no Gb3 accumulation in NSCs and neurons. Transmission electron microscopy did not reveal any zebra body‐like structures or inclusion bodies, which are characteristic of FD. These results indicated that neuronal cells derived from FD‐iPSCs exhibited normal morphology and no Gb3 accumulation. It is likely that more in vivo environment‐like cultures are needed for iPSC‐derived neurons to reproduce disease‐specific features.