Dystrophin deficiency affects human astrocyte properties andresponse to damage
Dystrophin deficiency affects human astrocyte properties andresponse to damage
复制标题
DOI：
10.1002/glia.24116
复制
发表时间：
2021-11-13
期刊：
影响因子：
6.2
通讯作者：
Ferretti, Patrizia
中科院分区：
文献类型：
--
作者：
Lange, Jenny;Gillham, Olivia;Ferretti, Patrizia
除了由于肌营养不良蛋白突变导致的进行性肌肉变性外，1/3的杜氏肌营养不良症（DMD）患者存在认知缺陷。然而，目前对多种肌营养不良蛋白亚型在人脑中的功能的了解还不完全。在这里，我们测试的假设，肌营养不良蛋白缺乏症影响神经胶质功能的DMD，因此可能有助于神经损伤。我们研究了人肌营养不良蛋白亚型的表达与发育和分化，以及对来自对照组和DMD患者的诱导多能干细胞的人星形胶质细胞损伤的反应。在对照细胞中，短肌营养不良蛋白亚型上调与发展和他们的表达水平变化不同的神经元和星形胶质细胞分化，以及在2维与3维星形胶质细胞培养。所有测试的DMD-星形胶质细胞显示改变的形态，增殖活性和AQP 4表达。此外，它们对炎症刺激没有表现出任何形态学变化，并且与刺激的健康星形胶质细胞相比，它们的数量显著降低。最后，DMD-星形胶质细胞似乎比对照组对氧化损伤更敏感，如其增加的细胞死亡所示。DMD-星形胶质细胞中的行为和代谢缺陷与具有不同突变的细胞系所共有的基因途径失调一致，如通过批量RNA-seq分析所证明的。总之，我们的DMD模型提供了DMD中星形胶质细胞功能改变的证据，表明星形胶质细胞反应缺陷可能导致神经损伤，并可能提供额外的潜在治疗靶点。
In addition to progressive muscular degeneration due to dystrophin mutations, 1/3 of Duchenne muscular dystrophy (DMD) patients present cognitive deficits. However, there is currently an incomplete understanding about the function of the multiple dystrophin isoforms in human brains. Here, we tested the hypothesis that dystrophin deficiency affects glial function in DMD and could therefore contribute to neural impairment. We investigated human dystrophin isoform expression with development and differentiation and response to damage in human astrocytes from control and induced pluripotent stem cells from DMD patients. In control cells, short dystrophin isoforms were up-regulated with development and their expression levels changed differently upon neuronal and astrocytic differentiation, as well as in 2-dimensional versus 3-dimensional astrocyte cultures. All DMD-astrocytes tested displayed altered morphology, proliferative activity and AQP4 expression. Furthermore, they did not show any morphological change in response to inflammatory stimuli and their number was significantly lower as compared to stimulated healthy astrocytes. Finally, DMD-astrocytes appeared to be more sensitive than controls to oxidative damage as shown by their increased cell death. Behavioral and metabolic defects in DMD-astrocytes were consistent with gene pathway dysregulation shared by lines with different mutations as demonstrated by bulk RNA-seq analysis. Together, our DMD model provides evidence for altered astrocyte function in DMD suggesting that defective astrocyte responses may contribute to neural impairment and might provide additional potential therapeutic targets.