The effects of A1/A2 astrocytes on oligodendrocyte linage cells against white matter injury under prolonged cerebral hypoperfusion
The effects of A1/A2 astrocytes on oligodendrocyte linage cells against white matter injury under prolonged cerebral hypoperfusion
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DOI：
10.1002/glia.23814
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发表时间：
2020-02-28
期刊：
影响因子：
6.2
通讯作者：
Hattori, Nobutaka
中科院分区：
文献类型：
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作者：
Miyamoto, Nobukazu;Magami, Shunsuke;Hattori, Nobutaka
由于少突胶质前体细胞（OPCs）易受缺血损伤，在慢性脑灌注不足时，它们向少突胶质细胞（OLG）的分化受损。星形胶质细胞-OLG相互作用对于白色物质的稳态是重要的。最近，反应性星形胶质细胞被分为两种类型，A1（细胞毒性）和A2（神经营养）。然而，它们在长期脑灌注不足中的作用仍不清楚。我们分析了低灌注下A1-A2星形胶质细胞和OPC-OLG之间相互作用的影响，重点是线粒体迁移。作为体内模型，使用微弹簧圈通过双侧颈总动脉狭窄（BCAS）建立慢性低灌注模型小鼠。作为匹配的体外研究，大鼠原代细胞与非致死浓度的氯化钴共培养。低灌注后28天，OPC和星形胶质细胞数量增加，而OLG减少。增加的星形胶质细胞主要为A1型星形胶质细胞，而A2型星形胶质细胞数量减少。在细胞培养中，OPC分化中断模拟慢性缺血，但星形胶质细胞条件培养基（ACM）后得到改善。然而，受损的ACM不能提高OPC成熟。与氯化钴孵育的星形胶质细胞从A2样A1样，线粒体迁移也减少。即使在高灌注条件下，Trk β激动剂也能够将星形胶质细胞从A1样维持到A2样，并通过细胞培养研究和BCAS模型中的线粒体迁移和药物作用来帮助OPC成熟和记忆障碍。A1样星形胶质细胞的减少可防止白色物质损伤。Trk β激动剂可能在慢性缺血性疾病的损伤中发挥重要作用。线粒体迁移可能是脑血管疾病的一个广泛的治疗策略。要点长时间的脑低灌注导致少突胶质细胞（oligodendrocyte，OLG）成熟受损和A1星形胶质细胞数量增加。线粒体迁移在体内/体外维持A2星形胶质细胞形态、成熟OLG和有髓鞘白色物质。
As oligodendrocyte precursor cells (OPCs) are vulnerable to ischemia, their differentiation to oligodendrocytes (OLG) is impaired in chronic cerebral hypoperfusion. Astrocyte-OLG interaction is important for white matter homeostasis. Recently, reactive astrocytes were separated into two types, A1 (cytotoxic) and A2 (neurotrophic). However, their role in prolonged cerebral hypoperfusion remains unclear. We analyzed the effects of interaction between A1-A2 astrocytes and OPC-OLG under hypoperfusion, focusing on mitochondrial migration. As an in vivo model, chronic hypoperfusion model mice were created by bilateral common carotid artery stenosis (BCAS) using microcoils. As a matching in vitro study, rat primary cells were cocultured with a nonlethal concentration of CoCl2. At 28 days after hypoperfusion, the number of OPC and astrocytes increased, whereas that of OLG decreased. Increased astrocytes were mainly A1-like astrocytes; however, the number of A2-like type decreased. In cell culture, OPC differentiation was interrupted under mimic chronic ischemia, but improved after astrocyte-conditioned medium (ACM) was added. However, injured-ACM was unable to improve OPC maturation. Incubation with CoCl2 changed astrocytes from A2-like to A1-like, and mitochondrial migration was also reduced. A Trk beta agonist was able to maintain astrocytes from A1-like to A2-like even under hyperperfused conditions, and aided in OPC maturation and memory impairment via mitochondrial migration and drug effects in cell culture study and BCAS model. The reduction of A1-like astrocytes protects against white matter injury. Trk beta agonists may play an important role in the impairment under chronic ischemic conditions. Mitochondrial migration may be a broad therapeutic strategy for cerebrovascular diseases.Main points Prolonged cerebral hypoperfusion leads to impaired oligodendrocyte (OLG) maturation and increased numbers of A1 astrocytes. Mitochondria migration maintained A2 astrocyte morphology, mature OLG, and myelinated white matter in vivo/vitro.