Applications of neural stem cells in spinal cord injury

我们的长期目标是发展有效的移植策略治疗脊髓损伤 使用定义明确的神经干细胞。尽管有替代细胞和修复受损CNS的潜力， 这种方法的治疗价值仍然未经证实。我们已经证明，谱系限制的前体 (NPC)由神经元和神经胶质限制性前体（分别为NRP和GRP）组成 来自转基因AP大鼠并用于可靠的命运分析。当移植到成年人的中枢神经系统， 并分化成不同的神经表型。NRP/GRP共同创建了一个微环境， 允许受损脊髓中的神经元分化并支持功能恢复。神经元 由NPC移植物产生的细胞与宿主组织整合，形成突触并投射出长轴突， 潜在地规避了受损宿主的不良再生能力。我们建议测试特定的 谱系限制的前体移植物可以重新填充脊髓损伤部位，整合 与宿主，促进发芽，髓鞘形成和宿主保护，并重建中断的连接， 与目标形成功能中继。因为NPC的属性很可能会受到宿主的影响 微环境，我们将测试特定的治疗机制在选定的损伤系统中的作用。在Aim中 1我们将继续我们的研究，通过检查NPC移植物如何在挫伤中恢复， 改变损伤环境以及恢复是否通过保留和发芽介导。在目标2中， 将测试移植衍生神经元与宿主建立主动连接并形成功能性神经元的能力。 切断的背柱轴突和它们的目标之间的中继，导致感觉缺陷的恢复。目的 3将检查NPC是否可以通过连接侧索损伤中的轴突来促进轴突生长。 切断的红核脊髓束和局部回路。鼻咽癌移植物的疗效及机制 将通过一系列行为和生理测试以及NPC表达的分析来检查 轮廓和移植物消融。为了使治疗效果最大化，NPC移植物将与 改善轴突生长的治疗方法，并通过微创技术进行测试。采取 总之，这些实验将检验我们的假设的具体要素， 血统限制了前体参与和促进恢复进程的多个阶段。

Our long term objectives are to develop effective transplantation strategies for treatment of spinal cord injury using well-defined neural stem cells. Despite the potential to replace cells and repair damaged CNS, the therapeutic value of this approach remains unproven. We have shown that lineage-restricted precursors (NPC) composed of neuronal and glial restricted precursors (NRP and GRP, respectively) can be isolated from transgenic AP rats and used for reliable fate analysis. When grafted into the adult CNS, they survive and differentiate into distinct neural phenotypes. Together the NRP/GRP create a micro-environment that allows robust neuronal differentiation in the injured spinal cord and support recovery of function. The neurons produced by the NPC graft integrate with host tissue, form synapses and project long axons that could potentially circumvent the poor regenerative capacity of the injured host. We propose to test specific hypotheses that grafts of lineage restricted precursors can repopulate the site of spinal cord injury, integrate with the host, promote sprouting, myelination and host protection, and reconstruct interrupted connections by forming functional relays with targets. Because the properties of the NPC are likely to be affected by the host microenvironment, we will test the role of specific therapeutic mechanisms in selected injury systems. In Aim 1 we will follow our studies that showed recovery in a contusion injury by examining how the NPC graft can modify the injury environment and whether recovery is mediated through sparing and sprouting. In Aim 2 we will test the ability of graft-derived neurons to establish active connections with the host and form a functional relay between the severed dorsal column axons and their target resulting in recovery of sensory deficits. Aim 3 will examine whether NPCs can promote axon growth in a lateral funiculus injury by connecting the axotomized rubrospinal tract and local circuits. The therapeutic efficacy and mechanisms of the NPC graft will be examined by a series of behavioral and physiological tests as well as analysis of the NPC expression profile and graft ablation. To maximize the therapeutic effects, the NPC grafts will be combined with treatments that improve axon growth and tested for delivery by a minimally invasive technique. Taken together, these experiments will test the specific elements of our hypothesis with respect to the role of lineage restricted precursors to participate and contribute to multiple stages of the recovery process.