Cellular and Molecular Interactions in the Aging SVZ Niche

描述（由申请人提供）：神经发生和向嗅球供应新神经元是目前唯一公认的成年脑室下区（SVZ）干细胞生态位在非损伤情况下的“再生”特征。我们提出了一个新的作用，成人脑干细胞-修复室管膜细胞衬里，覆盖的SVZ。在初步工作中，我们发现，随着年龄的增长，SVZ，成人大脑中最大的干细胞龛，显示出退化的迹象，新神经元的产生减少。然而，在SVZ的剩余部分，我们发现了强大的神经发生区域，即使在生命的后期。这些神经源性区域也显示出室管膜细胞壁的主动修复迹象，室管膜细胞壁覆盖在SVZ上，并将其与充满液体的脑腔（脑室）分开。室管膜细胞为SVZ提供保护屏障和过滤系统。在老年人的大脑中，我们检测到室管膜内插入的SVZ星形胶质细胞数量增加。这些星形胶质细胞与邻近的室管膜细胞形成粘附连接，并显示室管膜细胞的形态学和抗原特征;它们与室管膜标记物共标记，并具有多个纤毛，类似于室管膜细胞。有趣的是，最近发现SVZ的干细胞是SVZ星形胶质细胞的亚群。作为一个5年的计划，检查干细胞介导的修复老化的大脑，我们将测试的假设，SVZ干细胞有助于修复室管膜衬里的老年小鼠的心室。我们还将比较和对比年轻成年小鼠的损伤诱导修复与老年小鼠的年龄相关修复。我们认为室管膜修复只有在生命的后期才成为必要的，因为死亡的室管膜细胞或扩张的侧脑室留下的间隙需要填补。支持这一假设将扩展SVZ的再生功能，包括室管膜修复-第一个非神经元再生修复机制确定的干细胞的成人SVZ龛。

DESCRIPTION (provided by applicant): Neurogenesis and the supply of new neurons to the olfactory bulb is the only currently acknowledged 'regenerative' feature of the adult brain subventricular zone (SVZ) stem cell niche in a non-injury situation. We propose a novel role for adult brain stem cells-- repair of the ependymal cell lining that overlies the SVZ. In preliminary work we found that with age the SVZ, the largest stem cell niche in the adult brain, shows signs of deterioration with a reduction in the production of new neurons. However, in what remains of the SVZ, we find regions of robust neurogenesis, even late in life. These neurogenic zones also show signs of active repair to the ependymal cell wall that overlies the SVZ and separates it from the brain's fluid-filled cavities, the ventricles. Ependymal cells provide a protective barrier and filtration system for the SVZ. In the elderly brain, we detect increased numbers of SVZ astrocytes interposed within the ependyma. These astrocytes develop adherens junctions with neighboring ependymal cells and display morphologic and antigenic characteristics of ependymal cells; they co-label with ependymal markers and possess multiple cilia, similar to ependymal cells. Interestingly, the stem cells of the SVZ were recently found to be a subpopulation of SVZ astrocytes. As a 5-year plan to examine stem cell-mediated repair in the aging brain, we will test the hypothesis that SVZ stem cells contribute to repair of the ependymal lining of the ventricle in elderly mice. We will also compare and contrast injury-induced repair in young adult mice to age-related repair in elderly mice. We propose that ependymal repair becomes necessary only late in life when gaps, left by dying ependymal cells or an expanding lateral ventricle, need to be filled. Support for this hypothesis would extend the regenerative functions of the SVZ to include ependymal repair--the first non-neuronal mechanism of regenerative repair identified for stem cells of the adult SVZ niche.