Impairment of oligodendrocyte lineages in Spinal Muscular Atrophy Model Systems
Impairment of oligodendrocyte lineages in Spinal Muscular Atrophy Model Systems
复制标题
脊髓性肌萎缩模型系统中少突胶质细胞谱系的损伤
DOI：
10.1097/wnr.0000000000001206
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发表时间：
2019
期刊：
影响因子：
1.7
通讯作者：
Kaneko H and Hara H
中科院分区：
文献类型：
--
作者：
Ohuchi K;Funato M;Ando S;Inagaki S;Sato A;Kawase C;Seki J;Nakamura S;Shimazawa M;Kaneko H and Hara H
运动神经元存活缺陷表明脊髓性肌萎缩症（SMA）中多种细胞过程受损。先前的报道表明，SMN缺乏导致运动神经元变性，而在SMA模型系统中星形胶质细胞和小胶质细胞的数量显著增加或活化。只有少数几组研究了少突胶质细胞（OL）谱系，如OL前体细胞和神经/胶质抗原2（NG 2）-胶质细胞在SMA病理中的作用。我们在这项研究中的目的是调查是否OL谱系在SMA模型系统中受损。我们使用SMNΔ7小鼠（mSmn−/−、SMN 2 +/+、SMNΔ7+/+）和源自SMA患者产生的诱导多能干细胞的细胞培养物研究了髓鞘碱性蛋白（MBP）和NG 2（OL谱系标志物）的表达。我们首次表明，OL谱系，包括NG 2阳性OL前体细胞和MBP阳性髓鞘化OL在SMNΔ7小鼠和SMA患者诱导的多能干细胞中受损。Notch参与了SMNΔ7小鼠脊髓NG 2表达的下降。此外，药理学Notch抑制促进SMNΔ7小鼠中MBP阳性OL分化。这些结果表明，在SMA中OL分化受损，这可能涉及Notch失调。
Survival motor neuron (SMN) deficiency indicates that various cellular processes are impaired in spinal muscular atrophy (SMA). Previous reports have shown that SMN deficiency causes motor neuron degeneration, whereas the numbers of astrocytes and microglia are significantly increased or activated in SMA model systems. Only a few groups have studied the role of oligodendrocyte (OL) lineages such as OL precursor cell and nerve/glial antigen 2 (NG2)-glia in SMA pathology. Our aim in this study was to investigate whether OL lineages are impaired in SMA model systems. We investigated the expression of myelin basic protein (MBP) and NG2, which are OL lineage markers, using SMNΔ7 mice (mSmn−/−, SMN2+/+, SMNΔ7+/+) and cell cultures derived from induced pluripotent stem cells generated from SMA patients. We showed for the first time that the OL lineages, including NG2-positive OL precursor cells and MBP-positive myelinating OLs were impaired in SMNΔ7 mice and induced pluripotent stem cells derived from SMA patients. Notch was involved in the decline of NG2 expression in the spinal cord of SMNΔ7 mice. In addition, pharmacological Notch inhibition promoted MBP-positive OL differentiation in SMNΔ7 mice. These findings indicate that OL differentiation was impaired in SMA, which might be involved in the Notch dysregulation.