Migration of Human Neural Stem Cells In Vitro and In Vivo

描述（由申请人提供）：脑室下区（SVZ）已被证明是成年啮齿动物大脑中最大的生发区域。最近的研究也表明，成人脑SVZ不仅存在类似的神经发生区，而且其细胞结构也与成人SVZ不同：室管膜下存在细胞下间隙和星形胶质细胞带。目前尚不清楚人脑中的神经干细胞是否精确定位于成人SVZ的星形胶质细胞带中，以及这些成体神经干细胞是否具有迁移能力。究竟是什么调控了干细胞的迁移能力或脑肿瘤的转化尚不清楚，但表皮生长因子（EOF）参与了这一过程。在此背景下，我们将追求以下具体目标：目标1：精确定位成人神经干细胞相对于室管膜的位置，并将成人SVZ与胎儿SVZ和胶质瘤患者SVZ进行比较。假设干细胞集中在平行于室管膜的星形胶质细胞带中，当患者的胶质瘤邻近和/或部分脑室下区时，这种星形胶质细胞带更为突出；2)脑肿瘤患者的星形胶质细胞带内有大量的CD 133+细胞；3)胎儿SVZ中不存在这种星形胶质细胞带。目的2：通过体外迁移实验和体内啮齿动物模型，建立EGF在成人、胎儿和人类脑癌干细胞迁移能力中的作用。假设是，人类成体干细胞具有迁移能力，用EGF对其进行操作可以使其具有更强的迁移行为，类似于胎儿人脑和/或高级别肿瘤的迁移行为。这个项目与公共卫生直接相关。如果成体神经干细胞具有迁移能力，我们将进一步阐明人类大脑的自我修复能力，并可能找到使这些细胞迁移的方法，以取代那些因广泛的神经损伤或疾病而丢失的细胞。此外，神经干细胞和癌症干细胞可能具有相似的迁移和侵袭机制，了解这一机制可能有助于更好地治疗脑肿瘤。

DESCRIPTION (provided by applicant): The subventricular zone (SVZ) has been shown to be the largest germinal region in the adult rodent brain. Recent studies have also demonstrated not only that a similar neurogenic region exists in the SVZ of the adult human brain, but also that the cytoarchitecture is different in the human SVZ: a hypocellular gap and a ribbon of astrocytes is present under the ependyma. It remains unknown whether neural stem cells in the human brain are precisely localized in this ribbon of astrocytes lining the adult human SVZ and whether these adult neural stem cells have the ability to migrate. What exactly regulates the migratory capacity of stem cells or the transformation of brain tumors is not known, but epidermal growth factor (EOF) has been implicated in this process. Within this context we will pursue the following Specific Aims: Aim 1: To precisely localize the adult human neural stem cells with respect to the ependyma and to compare the adult human SVZ to the fetal human SVZ and to the SVZ of patients with gliomas. The hypothesis is that stem cells are concentrated in the band of astrocytes parallel to the ependyma and that this ribbon of astrocytes is 1) more prominent when patients have gliomas that are adjacent and/or part of the subventricular zone; 2) there is a larger population of CD 133+cells within this ribbon of astrocytes in patients with brain tumors 3) this ribbon of astrocytes does not exist in the fetal human SVZ. Aim 2: To establish the role of EGF in the migratory ability of adult, fetal, and human brain cancer stem cells using both in vitro migration assays and an in vivo rodent model. The hypothesis is that human adult stem cells have the ability to migrate and that their manipulation with EGF can change them to a more aggressive migratory behavior that resembles that of the fetal human brain and/or high grade tumors. This project has direct relevance to public health. If adult neural stem cells have the ability to migrate we will further elucidate the human brain's capacity for self-repair and may be able to figure out ways to make these cells migrate to replace those lost following extensive neuronal damage or disease. In addition, neural stem cells and cancer stem cells may share similar mechanisms of migration and invasion and understanding this mechanism may lead to better treatments of brain tumors.