Cellular and Molecular Interactions in the Aging SVZ Niche

描述(申请人提供)：神经发生和向嗅球供应新神经元是目前公认的成人脑室下区(SVZ)干细胞龛在非损伤情况下唯一的“再生”特征。我们为成人脑干细胞提出了一种新的作用--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，成年大脑中最大的干细胞区SVZ显示出恶化的迹象，新神经元的产生减少。然而，在SVZ的残留物中，我们发现了健壮的神经发生区域，即使在生命后期也是如此。这些神经源性区域也显示出室管膜细胞壁的积极修复迹象，室管膜细胞壁覆盖在SVZ上，将其与大脑充满液体的腔--脑室隔开。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贴壁连接，表现出室管膜细胞的形态和抗原特征；它们与室管膜标志物共标记，并具有与室管膜细胞相似的多纤毛。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。作为检验干细胞介导的老化脑修复的五年计划，我们将检验SVZ干细胞有助于老年小鼠脑室室管膜内膜修复的假设。我们还将比较和对比年轻成年小鼠的损伤诱导修复和老年小鼠的年龄相关修复。我们认为，室管膜修复术仅在晚年因室管膜细胞死亡或侧脑室扩张而留下的缝隙需要填补时才有必要。对这一假设的支持将扩展SVZ的再生功能，使其包括室管膜修复--这是在成年SVZ的壁龛干细胞中发现的第一种非神经元再生修复机制。

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.