Sporadic ALS Astrocytes Induce Neuronal Degeneration In Vivo.
Sporadic ALS Astrocytes Induce Neuronal Degeneration In Vivo.
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散发性 ALS 星形胶质细胞诱导体内神经元变性
DOI：
10.1016/j.stemcr.2017.03.003
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发表时间：
2017-04-11
影响因子：
5.9
通讯作者：
Zhang SC
中科院分区：
文献类型：
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作者：
Qian K;Huang H;Peterson A;Hu B;Maragakis NJ;Ming GL;Chen H;Zhang SC
来自家族性肌萎缩侧索硬化症（ALS）患者或转基因小鼠的星形胶质细胞对运动神经元（MN）具有特异性毒性。目前尚不清楚来自散发性ALS（sALS）患者的星形胶质细胞是否在体内引起MN变性以及该效应是否特异于MN。通过将来源于sALS和健康的诱导多能干细胞（iPSC）的脊髓神经祖细胞移植到成年SCID小鼠的颈髓中9个月，我们发现分化的人星形胶质细胞存在于脊髓的大面积中，取代内源性星形胶质细胞，并以类似的程度接触神经元。具有sALS而非非ALS细胞的小鼠显示出非MN数量减少，随后是宿主脊髓中的MN。存活的MNs表现出抑制性神经元的输入减少，并表现出神经丝紊乱和泛素聚集。相应地，具有sALS而非非ALS细胞的小鼠表现出下降的运动缺陷。因此，sALS iPSC衍生的星形胶质细胞在MN和非MN两者中引起ALS样变性。sALS iPSC衍生的星形胶质细胞广泛整合到成年脊髓中ALS iPSC衍生的星形胶质细胞比MN更早引起非MN的变性变性神经元表现出神经丝紊乱和聚集的泛素移植有sALS细胞的动物表现出运动行为缺陷在这篇文章中，Zhang，Chen及其同事表明，在通过将人iPSC衍生的神经祖细胞移植到成年小鼠脊髓中而创建的嵌合模型中，sALS星形胶质细胞在非MN中诱导ALS样变性，然后是MN。结果证明了sALS星形胶质细胞在体内的因果作用，并表明非MN在介导MN变性中的作用。
Astrocytes from familial amyotrophic lateral sclerosis (ALS) patients or transgenic mice are toxic specifically to motor neurons (MNs). It is not known if astrocytes from sporadic ALS (sALS) patients cause MN degeneration in vivo and whether the effect is specific to MNs. By transplanting spinal neural progenitors, derived from sALS and healthy induced pluripotent stem cells (iPSCs), into the cervical spinal cord of adult SCID mice for 9 months, we found that differentiated human astrocytes were present in large areas of the spinal cord, replaced endogenous astrocytes, and contacted neurons to a similar extent. Mice with sALS but not non-ALS cells showed reduced non-MNs numbers followed by MNs in the host spinal cord. The surviving MNs showed reduced inputs from inhibitory neurons and exhibited disorganized neurofilaments and aggregated ubiquitin. Correspondingly, mice with sALS but not non-ALS cells showed declined movement deficits. Thus, sALS iPSC-derived astrocytes cause ALS-like degeneration in both MNs and non-MNs. sALS iPSC-derived astrocytes integrate into the adult spinal cord extensively ALS iPSC-derived astrocytes cause degeneration of non-MNs earlier than MNs Degenerating neurons exhibit disorganized neurofilaments and aggregated ubiquitin Animals grafted with sALS cells exhibit motor behavioral deficits In this article, Zhang, Chen, and colleagues show that in the chimeric model created by transplanting human iPSC-derived neural progenitors into the adult mouse spinal cord, sALS astrocytes induced ALS-like degeneration in non-MNs followed by MNs. The results demonstrate the causal role of sALS astrocytes in vivo and suggest the role of non-MNs in mediating MN degeneration.