Applications of neural stem cells in spinal cord injury

我们的长期目标是开发有效的移植策略来治疗脊髓损伤。 使用定义明确的神经干细胞。尽管有可能替换细胞和修复受损的中枢神经系统，但 这种方法的治疗价值仍未得到证实。我们已经证明了血统限制的前体 可以分离出由神经元和神经胶质限制性前体(分别为NRP和GRP)组成的鼻咽癌 从转基因AP大鼠中提取并用于可靠的命运分析。当移植到成年中枢神经系统时，它们存活下来 并分化成不同的神经表型。NRP/GRP共同创造了一个微环境， 在受损的脊髓中允许强大的神经元分化，并支持功能的恢复。这些神经元 鼻咽癌移植物产生的产物与宿主组织结合，形成突触并投射出能够 潜在地绕过受伤宿主较差的再生能力。我们建议测试特定的 血统受限的前体细胞移植可以重新填充脊髓损伤部位的假说 与宿主一起，促进萌发、髓鞘形成和宿主保护，并通过以下方式重建中断的连接 与目标形成功能继电器。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 我们将继续我们的研究，通过检查鼻咽癌移植物如何在挫伤后恢复。 修改损伤环境，以及是否通过保留和萌发来调节恢复。在《目标2》中，我们 将测试移植物衍生的神经元与宿主建立主动连接并形成功能性连接的能力 切断的背柱轴突与其靶点之间的传递导致感觉缺陷的恢复。目标 3将研究在外侧索损伤中，npc是否可以通过连接 切断红核脊髓束和局部环路。鼻咽癌移植物的治疗效果及机制 将通过一系列行为和生理测试以及对NPC表达的分析进行检查 侧写和移植物消融。为了最大限度地发挥治疗效果，鼻咽癌移植物将与 促进轴突生长的治疗，并通过微创技术进行了交付测试。已被占用 总而言之，这些实验将测试我们假设的特定元素，涉及到 血统受限的前体参与恢复过程的多个阶段并做出贡献。

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.