MPTP-Induced Homing of Bone Marrow Stem Cells to the Br*

在成年哺乳动物中，骨髓来源的干细胞融入多种组织类型，在那里它们产生了跨越经典胚胎学三层边界的多种谱系的细胞[9,11,17,21,31,40,41]。这一最新发现开启了骨髓移植在临床上治疗多种疾病的可能性。最近，骨髓来源的祖细胞已被证明可以迁移并融入大脑，产生神经外胚层谱系的细胞（星形胶质细胞和神经元），以及小胶质细胞[4,7,25]。重要的是，骨髓来源的祖细胞似乎优先归巢到中枢神经系统胶质瘤和变性[8]区域，这与外周组织的研究结果一致，表明多潜能骨髓来源的干细胞在损伤部位的移植增强[21,31][Jackson, 2001 #360]。目前的研究重点是探索骨髓来源的干细胞在帕金森病啮齿动物模型（mptp治疗小鼠）中的迁移和分化。在这个提议中需要解决的问题包括：骨髓来源的祖细胞在mptp诱导的变性中是否表现出选择性归巢到受损的黑质和纹状体？如果是这样，它们会产生神经外胚层谱系的细胞吗？它们对伴随黑质纹状体变性的神经胶质瘤的作用是什么？为了追踪中枢神经系统内的骨髓源性祖细胞，我们将利用在β -肌动蛋白启动子下表达增强型绿色荧光蛋白（GFP）的转基因小鼠骨髓。骨髓源祖细胞的迁移和分化将在嵌合小鼠中进行研究，嵌合小鼠的内源性造血系统在MPTP治疗前已被表达GFP的细胞完全重建，在MPTP治疗前接受表达GFP+的细胞急性血管内注射的小鼠，以及在MPTP诱导的变性发生后接受表达GFP+的骨髓急性血管内注射的小鼠。提出的研究的直接目标是在帕金森病的啮齿动物模型中描述骨髓衍生祖细胞与大脑之间的关系。如果成功，这些研究可能为未来开发新的无创基因治疗帕金森病的工作提供基础，使用可获得的、可再生的和自体骨髓干细胞。

Bone marrow-derived stem cells incorporate into multiple tissue types in adult mammals, where they give rise to cells of multiple lineages that cross classic embryological trilaminar boundaries [9,11,17,21,31,40,41]. This recent discovery has opened the possibility that bone marrow transplantation could be clinically useful to treat a broad spectrum of pathologies. Recently, marrow-derived progenitor cells have been shown to migrate and incorporate into the brain to give rise to cells of neuroectodermal lineage, (astrocytes and neurons), in addition to microglia [4,7,25]. Importantly, marrow-derived progenitors appear to display preferential homing to regions of CNS gliosis and degeneration [8], consistent with studies in peripheral tissues demonstrating enhanced engraftment of multi-potential marrow-derived stem cells into sites of injury [21,31] [Jackson, 2001 #360]. The focus of the current proposal is to explore the migration and differentiation of marrow-derived stem cells into the brain in a rodent model of Parkinson's disease, the MPTP-treated mouse. Questions to be addressed in this proposal include: Do marrow-derived progenitors display selective homing to the damaged nigra and striatum in response to MPTP-induced degeneration? If so, do they give rise to cells of neuroectodermal lineage? What is their contribution to the gliosis that accompanies nigrostriatal degeneration? To track marrow-derived progenitors within the CNS, we will utilize bone marrow from transgenic mice that express an enhanced green fluorescent protein (GFP) under the beta-actin promoter. The migration and differentiation of marrow-derived progenitors will be studied in chimeric mice whose endogenous hematopoietic systems have been completely reconstituted with GFP-expressing cells prior to MPTP- treatment, and in mice that receive acute intravascular injections of GFP+ expressing cells prior to MPTP-treatment, and in mice that receive acute intravascular injections of GFP+ expressing marrow following the onset of MPTP-induced degeneration. The immediate goal of the proposed studies is to delineate the relationship between marrow-derived progenitors and the brain in a rodent model of Parkinson's disease. If successful, these studies may provide the basis for future work to development new non-invasive gene therapies for Parkinson's disease, using accessible, renewable and autologous bone marrow stem cells.