Cellular and Molecular Interactions in the Aging SVZ Niche

衰老 SVZ 生态位中的细胞和分子相互作用

• 批准号: 7389641
• 负责人: JOANNE C CONOVER
• 金额: $ 27.25万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7389641
• 关键词: Adherens Junction; Adult; Age; Age-Years; Aging; Aging-Related Process; Alkaline Phosphatase; Ara-C; Area; Astrocytes; Avian Leukosis Virus; Binding; Brain; Brain Injuries; Brain Stem; Bromodeoxyuridine; Cell Death; Cell Line; Cell Wall; Cells; Cerebrospinal Fluid; Cerebrum; Characteristics; Cilia; Deterioration; Development; Dorsal; Elderly; Ependyma; Ependymal Cell; Event; Filtration; Generations; Glial Fibrillary Acidic Protein; Image; Immunohistochemistry; In Situ Nick-End Labeling; Injury; Label; Left; Life; Link; Liquid substance; Measurement; Mechanics; Mediating; Monitor; Morphology; Mus; Neuraminidase; Neuroglia; Neurons; Numbers; Perinatal; Production; Proliferating; Radial; Reporter; Role; Scanning Transmission Electron Microscopy Procedures; Series; Stem cells; Surface; System; Tamoxifen; Techniques; Testing; Transgenic Mice; Week; Work; adult stem cell; age related; aging brain; base; brain cell; caspase-3; cell type; day; lateral ventricle; light microscopy; nerve stem cell; nervous system disorder; neurogenesis; novel; olfactory bulb; programs; repaired; young adult

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.

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公认的成人大脑室下区（SVZ）干细胞生态位在非损伤情况下唯一的“再生”特征。我们提出了成体脑干细胞的一个新作用——修复 SVZ 上的室管膜细胞衬里。在初步研究中，我们发现随着年龄的增长，成人大脑中最大的干细胞生态位 SVZ 会出现恶化迹象，新神经元的产生减少。然而，在 SVZ 的剩余部分中，我们发现了强大的神经发生区域，甚至在生命的晚期也是如此。这些神经源性区域还显示出室管膜细胞壁主动修复的迹象，室管膜细胞壁覆盖 SVZ，并将其与大脑充满液体的腔室（心室）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，并拥有多个纤毛，类似于室管膜细胞。有趣的是，最近发现 SVZ 干细胞是 SVZ 星形胶质细胞的一个亚群。作为一项研究干细胞介导的衰老大脑修复的五年计划，我们将测试 SVZ 干细胞有助于修复老年小鼠心室室管膜内壁的假设。我们还将比较和对比年轻成年小鼠的损伤诱导修复与老年小鼠的年龄相关修复。我们认为，只有在晚年，当室管膜细胞死亡或侧脑室扩张留下的间隙需要填补时，室管膜修复才变得必要。对这一假设的支持将扩展 SVZ 的再生功能，包括室管膜修复——为成人 SVZ 微环境干细胞确定的第一个非神经元再生修复机制。