Non-Cell-Autonomous Effect of Human SOD1G37R Astrocytes on Motor Neurons Derived from Human Embryonic Stem Cells
Non-Cell-Autonomous Effect of Human SOD1G37R Astrocytes on Motor Neurons Derived from Human Embryonic Stem Cells
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DOI：
10.1016/j.stem.2008.10.001
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发表时间：
2008-12-04
期刊：
影响因子：
23.9
通讯作者：
Gage, Fred H.
中科院分区：
文献类型：
--
作者：
Marchetto, Maria C. N.;Muotri, Alysson R.;Gage, Fred H.
肌萎缩侧索硬化症（ALS）是一种以运动神经元死亡为特征的神经退行性疾病。ALS可由超氧化物歧化酶1基因（SOD1）突变诱导。ALS的非细胞自主性质的证据来自于野生型神经胶质细胞延长嵌合小鼠中SOD1突变运动神经元的存活的观察。为了揭示星形胶质细胞对人运动神经元变性的贡献，我们将hESC衍生的运动神经元与表达突变的SOD1的人原代星形胶质细胞共培养。我们检测到一种选择性运动神经元毒性，这与SOD1突变的星形胶质细胞的炎症反应增加有关。此外，我们提出的证据表明，星形胶质细胞可以激活NOX2产生超氧化物，这种作用可以被抗氧化剂逆转。我们表明，NOX2抑制剂，夹竹桃苷，可以防止由SOD 1突变的星形胶质细胞引起的运动神经元的损失。这些结果提供了使用人ALS体外星形胶质细胞为基础的细胞模型进行药物筛选的测定。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron death. ALS can be induced by mutations in the superoxide dismutase 1 gene (SOD1). Evidence for the non-cell-autonomous nature of ALS emerged from the observation that wild-type glial cells extended the survival of SOD1 mutant motor neurons in chimeric mice. To uncover the contribution of astrocytes to human motor neuron degeneration, we cocultured hESC-derived motor neurons with human primary astrocytes expressing mutated SOD1. We detected a selective motor neuron toxicity that was correlated with increased inflammatory response in SOD1-mutated astrocytes. Furthermore, we present evidence that astrocytes can activate NOX2 to produce superoxide and that effect can be reversed by antioxidants. We show that NOX2 inhibitor, apocynin, can prevent the loss of motor neurons caused by SOD1-mutated astrocytes. These results provide an assay for drug screening using a human ALS in vitro astrocyte-based cell model.