TRANSPLANTATION OF HUMAN BONE MARROW STROMAL CELLS

描述(由申请人提供)： 这项建议的重点是干细胞最新进展的应用。 生物学为脊髓损伤提供了一种潜在的治疗方法。建议数 实验将利用从人骨髓中提取的间充质干细胞 (骨髓基质细胞，hMSCs)，检测其表型如下 脊髓内移植并检测其促进能力 功能的再生和恢复。人骨髓间充质干细胞很容易从 患者在局部麻醉下，提供更新人口并可使用 用于自体移植。我们的初步数据显示，hMSCs移植到 脊髓损伤存活，融合良好，看起来是允许的 轴突生长，因此是用于脊柱核心修复的极佳候选者 战略。HMSCs分化的全部潜能还不是很好。 我明白，但越来越多的证据表明，来自骨髓的成体细胞 具有显著的可塑性，并可以根据不同的 他们所遇到的环境。我们推测，通过移植hMSCs 细胞进入脊髓我们可以结合系统和直接的检查 并对其治疗效果进行了详细的分析。 井中神经元的挽救、轴突再生和功能恢复 脊髓损伤的特征性模型。以前的研究和我们的 初步数据表明，hMSCs产生多种细胞因子和 支持生存和再生的神经营养因子。建议数 实验将检测未经处理和处理的hMSCs在正常情况下的行为 脊髓(AIM 1)和一种典型的单侧脊髓损伤模型 C4损伤脊髓(AIM)2例。这些细胞将根据以下方面进行分析 它们的生存、迁徙和表型以及它们的救援能力 切断轴突的神经元(红核)，促进轴突再生( 皮质脊髓和红核脊髓束)和恢复功能(使用圆柱体， 绳索和栅格行走、伸展和去除补丁测试)。治疗性 然后，不同批次的hMSCs的潜能将与其 分泌因子的表达谱。在目标3中，我们将研究 移植的人骨髓间充质干细胞向伤者传递治疗性基因(BDNF和NT3) 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。综上所述，这些实验将提供一个 人骨髓间充质干细胞的特性及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.