Ephrin-A1-mediated dopaminergic neurogenesis and angiogenesis in a rat model of Parkinson's disease.
Ephrin-A1-mediated dopaminergic neurogenesis and angiogenesis in a rat model of Parkinson's disease.
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DOI：
10.1371/journal.pone.0032019
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Sakaguchi K
中科院分区：
文献类型：
--
作者：
Jing X;Miwa H;Sawada T;Nakanishi I;Kondo T;Miyajima M;Sakaguchi K
成人脑室下区（SVZ）中的神经干细胞谱系的细胞通过增加其数量并通过头端迁移流迁移来应对脑损伤。然而，在除了 SVZ 和齿状回颗粒下区之外的大脑大部分区域，这种再生反应极其微弱。即使这两个神经源性区域也没有表现出广泛的再生反应来修复组织损伤，这表明干细胞存在内在的抑制性微环境（生态位）。在本研究中，我们评估了将簇状肝配蛋白-A1-Fc注射到单侧黑质纹状体多巴胺耗竭大鼠的侧脑室中的效果。将抗IgG(Fc)抗体簇集的Ephrin-A1-Fc立体定位注射至6-羟基多巴胺诱导的单侧黑质纹状体病变大鼠的同侧侧脑室，并进行组织学分析和行为学测试。聚集的肝配蛋白-A1-Fc改变了心室下生态位，增加了心室下区域的溴脱氧尿苷阳性细胞，然后这些细胞迁移到纹状体并分化为多巴胺能神经元和星形胶质细胞。此外，聚集的肝配蛋白-A1-Fc 增强了注射侧纹状体的血管生成。随着组织学的改善，行为紊乱也显着改善。这些发现表明，心室下微环境具有通过 EphA 介导的信号调节干细胞和血管生成反应的机制。我们得出的结论是，侧脑室内聚集的肝配蛋白-A1-Fc 激活 EphA 受体介导的信号传导可能可用于治疗帕金森病等神经退行性疾病。
Cells of the neural stem cell lineage in the adult subventricular zone (SVZ) respond to brain insult by increasing their numbers and migrating through the rostral migratory stream. However, in most areas of the brain other than the SVZ and the subgranular zone of the dentate gyrus, such a regenerative response is extremely weak. Even these two neurogenic regions do not show extensive regenerative responses to repair tissue damage, suggesting the presence of an intrinsic inhibitory microenvironment (niche) for stem cells. In the present study, we assessed the effects of injection of clustered ephrin-A1-Fc into the lateral ventricle of rats with unilateral nigrostriatal dopamine depletion. Ephrin-A1-Fc clustered by anti-IgG(Fc) antibody was injected stereotaxically into the ipsilateral lateral ventricle of rats with unilateral nigrostriatal lesions induced by 6-hydroxydopamine, and histologic analysis and behavioral tests were performed. Clustered ephrin-A1-Fc transformed the subventricular niche, increasing bromodeoxyuridine-positive cells in the subventricular area, and the cells then migrated to the striatum and differentiated to dopaminergic neurons and astrocytes. In addition, clustered ephrin-A1-Fc enhanced angiogenesis in the striatum on the injected side. Along with histologic improvements, behavioral derangement improved dramatically. These findings indicate that the subventricular niche possesses a mechanism for regulating both stem cell and angiogenic responses via an EphA–mediated signal. We conclude that activation of EphA receptor–mediated signaling by clustered ephrin-A1-Fc from within the lateral ventricle could potentially be utilized in the treatment of neurodegenerative diseases such as Parkinson's disease.
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25
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Denise, A;Garcia, R;Sofroniew, MV
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Sofroniew, MV
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