Migration of Human Neural Stem Cells In Vitro and In Vivo

描述（由申请人提供）：室管膜下区（SVZ）已被证明是成年啮齿动物大脑中最大的生发区。最近的研究还表明，不仅存在于成年人大脑的SVZ中的类似的神经原性区域，而且在人类SVZ中的细胞结构是不同的：室管膜下存在细胞减少的间隙和星形胶质细胞的带状物。目前尚不清楚人类大脑中的神经干细胞是否精确地定位于成年人SVZ衬里的星形胶质细胞带中，以及这些成年神经干细胞是否具有迁移能力。究竟是什么调节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（EGF）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和比较成人SVZ胎儿人SVZ和SVZ的神经胶质瘤患者。假设干细胞集中在平行于室管膜的星形胶质细胞带中，并且星形胶质细胞带1）当患者具有邻近脑室下区和/或脑室下区的一部分的胶质瘤时更突出; 2）在患有脑肿瘤的患者中，在星形胶质细胞带内存在较大的CD 133+细胞群体3）这种星形胶质细胞带在胎儿人SVZ中不存在。目标二：通过体外迁移试验和体内啮齿动物模型，确定EGF在成人、胎儿和人脑癌干细胞迁移能力中的作用。该假说是，人类成体干细胞具有迁移能力，并且它们与EGF的操作可以将它们改变为更积极的迁移行为，类似于胎儿人脑和/或高级别肿瘤的迁移行为。该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，以取代那些在广泛的神经元损伤或疾病后丢失的细胞。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，了解这种机制可能会导致更好的脑肿瘤治疗。

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.