Migration of Human Neural Stem Cells In Vitro and In Vivo

描述(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。最近的研究还表明，不仅在成人脑的SVZ中存在类似的神经源性区域，而且人的SVZ的细胞结构也不同：室管膜下存在一个低细胞间隙和一条星形胶质细胞带。目前尚不清楚人脑中的神经干细胞是否准确地定位于成人SVZ内的星形胶质细胞带中，以及这些成人神经干细胞是否具有迁移能力。目前尚不清楚是什么确切地调节了干细胞的迁移能力或脑肿瘤的转化，但表皮生长因子(EOF)已经参与了这一过程。在这一背景下，我们将追求以下具体目标：目标1：准确定位成人神经干细胞在室管膜中的位置，并将成人SVZ与胎儿SVZ和胶质瘤患者的SVZ进行比较。假设干细胞集中在与室管膜平行的星形胶质细胞带中，1)当患者患有邻近和/或部分室下区的胶质瘤时，这条星形胶质细胞带更加突出；2)在脑肿瘤患者的这条星形胶质细胞带中有更多的CD 133+细胞；3)这条星形胶质细胞带在胎儿人的SVZ中不存在。目的：通过体外迁移实验和体内啮齿动物模型研究EGF在成人、胎儿和人脑肿瘤干细胞迁移能力中的作用。假设人类成年干细胞具有迁移的能力，并且通过对EGF的操作可以将它们改变为更具侵略性的迁移行为，类似于胎儿大脑和/或高级别肿瘤的迁移行为。该项目与公共卫生有直接关系。如果成人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，并可能找到让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，了解这一机制可能会导致脑肿瘤的更好治疗。

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.