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合到多种组织类型中，在那里它们产生跨越经典胚胎三层边界的多个谱系的细胞[9，11，17，21，31，40，41]。这一最新发现开启了骨髓移植可能在临床上用于治疗广泛的病理范围的可能性。最近，骨髓来源的前体细胞被证明除了小胶质细胞外，还可以迁移并合并到大脑中，形成神经外胚层细胞(星形胶质细胞和神经元)[4，7，25]。重要的是，骨髓来源的前体细胞似乎表现出对中枢神经系统胶质细胞增殖区和退行性变区域的优先归宿[8]，这与对周围组织的研究一致，表明多潜能的骨髓来源干细胞增强了对损伤部位的植入[21，31][Jackson，2001#360]。目前这项提议的重点是探索骨髓来源的干细胞在帕金森氏病啮齿动物模型--MPTP治疗的小鼠中的迁移和分化。这项提案中要解决的问题包括：骨髓来源的祖细胞是否对MPTP诱导的变性表现出选择性地归巢到受损的黑质和纹状体？如果是，它们会产生神经外胚层血统的细胞吗？它们对黑质纹状体退行性变引起的胶质细胞增多症有何贡献？为了在中枢神经系统内追踪骨髓来源的祖细胞，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)的转基因小鼠的骨髓。将在嵌合小鼠、在MPTP治疗前接受GFP+表达细胞的急性血管内注射的小鼠以及在MPTP诱导的变性开始后接受GFP+表达骨髓的急性血管内注射的小鼠中，研究骨髓来源的祖细胞的迁移和分化。这项拟议研究的直接目标是描绘帕金森氏症啮齿动物模型中骨髓祖细胞和大脑之间的关系。如果成功，这些研究可能为未来的工作提供基础，开发新的非侵入性帕金森病基因疗法，使用可获得的、可再生的和自体的骨髓干细胞。

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.