Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes
Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes
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DOI：
10.1523/jneurosci.1643-16.2016
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发表时间：
2016-10-12
影响因子：
5.3
通讯作者：
Martino, Gianvito
中科院分区：
文献类型：
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作者：
Bacigaluppi, Marco;Russo, Gianluca Luigi;Martino, Gianvito
缺血性中风是残疾的主要原因，但目前广泛缺乏有效的治疗方法。中风的恢复在很大程度上取决于开发治疗方法的可能性，这些治疗方法既能阻止神经退行性过程，又能促进适应性组织可塑性。在这里，我们表明，缺血小鼠神经前体细胞（NPC）移植治疗的神经生理学分析，治疗后早期，减少突触前释放的谷氨酸在同侧皮质脊髓束（CST），并增强NMDA介导的兴奋性传递在contralesional CST。同时，NPC治疗的小鼠表现出减少CST变性，增加轴突重新布线，并增强树突状分支，导致长期的功能改善持续到缺血后60天。增强的功能和结构可塑性依赖于移植的NPC定位于缺血周围和缺血区域的能力，以促进星形胶质细胞上的胶质细胞谷氨酸转运蛋白1（GLT-1）的上调，并减少缺血周围的细胞外谷氨酸。移植的NPC诱导的GLT-1的上调被发现依赖于NPC分泌VEGF。在中风后第一周阻断VEGF减少了NPC治疗小鼠中GLT-1的上调以及长期行为恢复。我们的研究结果表明，NPC移植，通过调节兴奋-抑制平衡和中风微环境，是一种有前途的治疗，以改善残疾，促进组织恢复和可塑性过程后中风。
Ischemic stroke is the leading cause of disability, but effective therapies are currently widely lacking. Recovery from stroke is very much dependent on the possibility to develop treatments able to both halt the neurodegenerative process as well as to foster adaptive tissue plasticity. Here we show that ischemic mice treated with neural precursor cell (NPC) transplantation had on neurophysiological analysis, early after treatment, reduced presynaptic release of glutamate within the ipsilesional corticospinal tract (CST), and an enhanced NMDA-mediated excitatory transmission in the contralesional CST. Concurrently, NPC-treated mice displayed a reduced CST degeneration, increased axonal rewiring, and augmented dendritic arborization, resulting in long-term functional amelioration persisting up to 60 d after ischemia. The enhanced functional and structural plasticity relied on the capacity of transplanted NPCs to localize in the peri-ischemic and ischemic area, to promote the upregulation of the glial glutamate transporter 1 (GLT-1) on astrocytes and to reduce peri-ischemic extracellular glutamate. The upregulation of GLT-1 induced by transplanted NPCs was found to rely on the secretion of VEGF by NPCs. Blocking VEGF during the first week after stroke reduced GLT-1 upregulation as well as long-term behavioral recovery in NPC-treated mice. Our results show that NPC transplantation, by modulating the excitatory-inhibitory balance and stroke microenvironment, is a promising therapy to ameliorate disability, to promote tissue recovery and plasticity processes after stroke.