TRANSPLANTATION OF HUMAN BONE MARROW STROMAL CELLS

描述（由申请人提供）： 这项建议的重点是应用最新进展的干细胞 生物学对脊髓损伤的潜在治疗。 拟议 实验将利用来自人类骨髓的间充质干细胞 （骨髓基质细胞，hMSCs），检查其表型， 移植到脊髓中，并测试它们促进 再生和功能恢复。 人MSC很容易从 局部麻醉下的患者，提供更新人群，并可用于 用于自体移植 我们的初步数据表明，hMSCs移植到 脊髓损伤存活，整合良好，似乎允许 轴突生长，因此是用于脊髓核心修复的极好候选者 战略布局 hMSCs分化的全部潜力并不好 但越来越多的证据表明，来自骨髓的成体细胞 具有显着的可塑性，并可以采取不同的表型依赖于 他们遇到的环境。 我们推断通过移植hMSCs 我们可以将联合收割机与系统的直接检查 它们在体内的命运，并详细分析了它们在 井中的神经元拯救、轴突再生和功能恢复 脊髓损伤的特征模型。 以前的研究和我们的 初步数据表明hMSC产生多种细胞因子， 支持存活和再生的神经营养因子。 拟议 实验将检查未处理和处理的hMSC在正常人中的行为， 脊髓（AIM 1），并在一个充分表征的损伤模型的单侧 C4损伤脊髓（AIM 2）。 这些细胞将被分析， 它们的生存、迁移和表型以及它们拯救 轴突切断的神经元（在红核中），促进轴突再生（ 皮质脊髓束和红核脊髓束）并恢复功能（使用圆柱体， 绳索和网格行走、到达和贴片移除测试）。治疗 不同批次的hMSC的潜力将与它们的 分泌因子的表达谱。 在目标3中，我们将研究 移植的hMSCs将治疗基因（BDNF和NT3）输送到受伤的人， 基因修饰对表型的影响 这些细胞的性质和修复和恢复的潜力， 功能 综合起来，这些实验将提供一个通过 hMSC的性质和治疗潜力的临床前分析， 受伤的CNS

DESCRIPTION (provided by applicant): This proposal is focused on application of recent advances in stem cell biology to a potential therapy for spinal cord injury. The proposed experiments will utilize mesenchymal stem cells derived from human bone marrow (marrow stromal cells, hMSCs), examine their phenotype following transplantation into spinal cord and test their ability to promote regeneration and recovery of function. Human MSCs are easy to obtain from a patient under local anesthesia, provide a renewal population and can be used for autologous grafting. Our preliminary data show that hMSCs grafted into spinal cord lesions survive, integrate well and appear to be permissive for axonal growth, and thus are excellent candidates for use in spinal core repair strategies. The full potential of hMSCs to differentiate is not well understood, but there is growing evidence that adult cells from bone marrow have remarkable plasticity and can assume diverse phenotypes dependent on the environment that they encounter. We reasoned that by transplanting hMSCs cells into spinal cord we can combine a systematic and direct examination of their fate in vivo with a detailed analysis of their therapeutic effects in neuronal rescue, axon regeneration and functional recovery in a well characterized model of spinal cord injury. Previous studies and our preliminary data suggest that hMSCs produce a variety of cytokines and neurotrophic factors that support survival and regeneration. The proposed experiments will examine the behavior of untreated and treated hMSCs in normal spinal cord (AIM 1) and in a well-characterized injury model of a unilateral C4 lesioned spinal cord (AIM 2). These cells will be analyzed with respect to their survival, migration and phenotype as well as their ability to rescue axotomized neurons (in the Red Nucleus), promote axon regeneration (of corticospinal and rubrospinal tracts) and restore function (using cylinder, rope and grid walking, reaching and patch removal tests). The therapeutic potential of different batches of hMSCs will then be correlated to their expression profile of secretory factors. In Aim 3 we will study the ability of grafted hMSCs to deliver therapeutic genes (BDNF and NT3) to the injured spinal cord and the effects of the genetic modification on the phenotypic properties of these cells and the potential for repair and restoration of function. Taken together, these experiments will provide a through preclinical analysis of the properties and therapeutic potential of hMSCs in the injured CNS.