Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury
Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury
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DOI：
10.1172/jci42957
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发表时间：
2010-09-01
影响因子：
15.9
通讯作者：
Nakashima, Kinichi
中科院分区：
文献类型：
--
作者：
Abematsu, Masahiko;Tsujimura, Keita;Nakashima, Kinichi
在受伤的中枢神经系统中，身体恢复受损神经网络的能力严重有限。尽管各种治疗方案可以部分缓解脊髓损伤（SCI），但症状改善的机制仍然难以捉摸。在这里，我们使用脊髓损伤小鼠模型，我们已经证明神经干细胞（NSCs）移植和丙戊酸（VPA），一种已知的抗癫痫和组蛋白去乙酰化酶抑制剂，显著增强后肢功能的恢复。VPA处理促进移植的NSCs向神经元而非胶质细胞分化。经突触顺行皮质脊髓束示踪显示，移植来源的神经元重建了断裂的神经元回路，电镜分析显示，移植来源的神经元既接受突触连接，也向内源性神经元发送突触连接。对移植细胞进行消融后，后肢运动功能恢复消失，证实NSC移植直接促进了后肢运动功能的恢复。这些发现提出了一种可能性，即移植的NSCs的表观遗传状态可以被操纵，从而为脊髓损伤提供有效的治疗。
The body's capacity to restore damaged neural networks in the injured CNS is severely limited. Although various treatment regimens can partially alleviate spinal cord injury (SCI), the mechanisms responsible for symptomatic improvement remain elusive. Here, using a mouse model of SCI, we have shown that transplantation of neural stem cells (NSCs) together with administration of valproic acid (VPA), a known antiepileptic and histone deacetylase inhibitor, dramatically enhanced the restoration of hind limb function. VPA treatment promoted the differentiation of transplanted NSCs into neurons rather than glial cells. Transsynaptic anterograde corticospinal tract tracing revealed that transplant-derived neurons reconstructed broken neuronal circuits, and electron microscopic analysis revealed that the transplant-derived neurons both received and sent synaptic connections to endogenous neurons. Ablation of the transplanted cells abolished the recovery of hind limb motor function, confirming that NSC transplantation directly contributed to restored motor function. These findings raise the possibility that epigenetic status in transplanted NSCs can be manipulated to provide effective treatment for SCI.