TRANSPLANTATION OF HUMAN BONE MARROW STROMAL CELLS

描述（由申请人提供）： 该提案的重点是干细胞最新进展的应用 生物学为脊髓损伤的潜在治疗方法。 拟议的 实验将利用源自人类骨髓的间充质干细胞 （骨髓基质细胞，hMSC），检查其表型如下 移植到脊髓并测试其促进能力 再生和功能恢复。 人类 MSC 很容易从 局部麻醉下的患者，提供更新群体并可使用 用于自体移植。 我们的初步数据显示 hMSCs 移植到 脊髓损伤能够存活、整合良好并且似乎允许 轴突生长，因此是用于脊髓核心修复的优秀候选者 策略。 hMSC 的全部分化潜力尚不充分 理解，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，可以呈现不同的表型 他们遇到的环境。 我们推断通过移植 hMSC 细胞进入脊髓，我们可以结合系统和直接的检查 他们在体内的命运以及对其治疗效果的详细分析 井中的神经元救援、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 支持生存和再生的神经营养因子。 拟议的 实验将检查未处理和处理过的 hMSC 在正常情况下的行为 脊髓 (AIM 1) 和单侧损伤模型 C4 脊髓损伤 (AIM 2)。 这些细胞将被分析为 它们的生存、迁徙和表型以及救援能力 轴突神经元（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、伸展和补丁去除测试）。治疗性的 不同批次 hMSC 的潜力将与其相关 分泌因子的表达谱。 在目标 3 中我们将研究能力 移植 hMSCs 将治疗基因（BDNF 和 NT3）传递给受伤者 脊髓及其基因修饰对表型的影响 这些细胞的特性以及修复和恢复的潜力 功能。 总而言之，这些实验将提供一个完整的 hMSCs 的特性和治疗潜力的临床前分析 受伤的中枢神经系统。

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.