Cellular and Molecular Interactions in the Aging SVZ Niche

描述（由申请人提供）：神经发生和向嗅球提供新神经元是目前唯一公认的成人脑室下区（SVZ）干细胞生态位在非损伤情况下的“再生”特征。我们提出了成人脑干细胞的一个新作用——修复覆盖在SVZ上的室管膜细胞衬里。在初步工作中，我们发现随着年龄的增长，成人大脑中最大的干细胞龛SVZ随着新神经元的产生减少而出现退化的迹象。然而，在残存的SVZ中，我们发现了强健的神经发生区域，甚至在生命后期也是如此。这些神经源性区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，并将其与大脑充满液体的腔室（脑室）分开。室管膜细胞为SVZ提供了保护屏障和过滤系统。在老年大脑中，我们发现室管膜内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，并表现出室管膜细胞的形态和抗原特征；它们与室管膜标记物共同标记，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星形胶质细胞的一个亚群。作为一项为期5年的计划，我们将研究干细胞介导的脑老化修复，我们将验证SVZ干细胞有助于老年小鼠脑室室管膜内衬修复的假设。我们还将比较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。我们建议，只有当室管膜细胞死亡或侧脑室扩张留下的空隙需要填补时，室管膜修复才有必要。对这一假设的支持将扩展SVZ的再生功能，包括室管膜修复——这是成人SVZ干细胞再生修复的第一个非神经元机制。

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.