The role of oligodendrocyte precursor cells expressing the GPR17 receptor in brain remodeling after stroke.
The role of oligodendrocyte precursor cells expressing the GPR17 receptor in brain remodeling after stroke.
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DOI：
10.1038/cddis.2017.256
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发表时间：
2017-06-08
影响因子：
9
通讯作者：
Abbracchio MP
中科院分区：
文献类型：
--
作者：
Bonfanti E;Gelosa P;Fumagalli M;Dimou L;Viganò F;Tremoli E;Cimino M;Sironi L;Abbracchio MP
在卒中诱导的神经元损伤后，静止的少突胶质前体细胞(OPC)被激活增殖，然后分化为髓鞘生成细胞。Gpr17是一种在早期OPC上瞬时表达的受体，已成为通过刺激OPC成熟来实现卒中修复的靶点。然而，由于GPR17在产生髓鞘的少突胶质细胞中完全下调，它在决定脑缺血后OPC最终命运方面的实际作用仍不确定。在这里，为了明确表达GPR17的OPC的时空变化和最终命运，我们用报告GPR17iCreERT2：CAG-E绿色荧光蛋白(GFP)的小鼠大脑中动脉闭塞(MCAO)诱导缺血，在GPR17iCreERT2：CAG-E绿色荧光蛋白(GFP)小鼠中，表达GPR17的细胞变绿，并且终身可追踪。DNA合成标记物5-溴-2‘-脱氧尿嘧啶核苷(BrdU)共标记显示，从MCAO后3d至2周，GFP+细胞在缺血灶周围明显聚集，部分GFP+细胞增殖。几乎所有的GFP+/BrdU+细胞都表达OPC早期标志物神经/神经胶质抗原2(NG2)，表明它们仍然是前体细胞。GFP+细胞的积累也是由于OPC从周围区域招募而来，正如体内通过获取典型的OPC迁移特征所表明的那样，在体外显示在存在化学诱导剂PDGF-AA的情况下，并通过将GFP+-OPC移植到野生型MCAO小鼠中证实了这一点。MCAO后8周，这些早熟招募的细胞中只有一些经历了成熟，表现为NG2的丢失和成熟的髓鞘标志物的获得，如GSTpi。一批招募的GFP+-OPC被保留在前身阶段，以可能使其可用于进一步侮辱。因此，缺血后非常早期，GFP+-OPC增殖并向病变迁移；然而，这些细胞大多仍未分化，提示除髓鞘形成外的其他功能作用。
Following stroke-induced neuronal damage, quiescent oligodendrocyte precursors (OPCs) are activated to proliferate and later to differentiate to myelin-producing cells. GPR17, a receptor transiently expressed on early OPCs, has emerged as a target to implement stroke repair through stimulation of OPC maturation. However, being GPR17 completely downregulated in myelin-producing oligodendrocytes, its actual role in determining the final fate of OPCs after cerebral ischemia is still uncertain. Here, to univocally define the spatiotemporal changes and final fate of GPR17-expressing OPCs, we induced ischemia by middle cerebral artery occlusion (MCAo) in reporter GPR17iCreERT2:CAG-eGreen florescent protein (GFP) mice, in which, upon tamoxifen treatment, cells expressing GPR17 become green and traceable for their entire life. Starting from 3 days and up to 2 weeks after MCAo, GFP+ cells markedly accumulated in regions surrounding the ischemic lesion; several of them proliferated, as shown by co-labeling of the DNA synthesis marker 5-Bromo-2′-deoxyuridine (BrdU). Almost all GFP+/BrdU+ cells expressed the OPC early marker neural/glial antigen 2 (NG2), indicating that they were still precursors. Accumulation of GFP+ cells was also because of OPC recruitment from surrounding areas, as suggested in vivo by acquisition of typical features of migrating OPCs, shown in vitro in presence of the chemoattractant PDGF-AA and confirmed by transplantation of GFP+-OPCs in wild-type MCAo mice. Eight weeks after MCAo, only some of these precociously recruited cells had undergone maturation as shown by NG2 loss and acquisition of mature myelinating markers like GSTpi. A pool of recruited GFP+-OPCs was kept at a precursor stage to likely make it available for further insults. Thus, very early after ischemia, GFP+-OPCs proliferate and migrate toward the lesion; however, most of these cells remain undifferentiated, suggesting functional roles other than myelination.
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