Origins, properties, and therapeutic potential of cells that repopulate the micro

重新填充微细胞的起源、特性和治疗潜力

• 批准号: 8695963
• 负责人: Kim Green
• 金额: $ 32.25万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695963
• 关键词: 3xTg-AD mouse; Address; Adult; Alzheimer' s Disease; Anti-Inflammatory Agents; Anti-inflammatory; Appearance; Brain; Bromodeoxyuridine; CCL2 gene; CCL3 gene; CD34 gene; CX3CL1 gene; Cell Death; Cells; Central Nervous System Diseases; Chronic; Clinical Trials; Cognition; Data; Dependence; Dependency; Development; Disease; Disease model; Embryonic Development; Flow Cytometry; Gene Expression; Genes; Genetic; Hour; ITGAX gene; Impaired cognition; Inflammation; Inflammatory; Investigation; Label; Life; Macrophage Colony-Stimulating Factor Receptor; Malignant Neoplasms; Messenger RNA; Microglia; Molecular Profiling; Morphology; Mus; Myelogenous; Neurodegenerative Disorders; PTPRC gene; Pathogenesis; Pathology; Peripheral; Phagocytosis; Phenotype; Physiological; Plastics; Play; Population; Proliferating; Property; RANTES; Receptor Inhibition; Receptor Signaling; Recovery; Regulation; Rest; Role; Signal Pathway; Signal Transduction; Source; Staining method; Stains; Stem cells; Therapeutic; Time; Wild Type Mouse; Withdrawal; age related; aged; aging brain; cell type; improved; inhibitor/antagonist; macrophage; mind control; mouse model; nestin protein; neuroinflammation; progenitor; public health relevance; self-renewal; senescence

DESCRIPTION (provided by applicant): Microglia are implicated in most disorders of the CNS, and while they offer protective roles in aspects of disease, their chronic activation and presence can impede recovery and promote cellular damage and cognitive decline. As such, anti-inflammatory strategies have been pursued as potential therapeutics to many neurodegenerative diseases, but have lacked potency. As part of our investigations into inflammation in the pathogenesis of Alzheimer's disease we targeted the colony-stimulating factor 1 receptor (CSF1R), as this regulates the proliferation of microglia. We discovered that microglia are actually physiologically dependent upon CSF1R signaling, and that administration of CSF1R antagonists results in the rapid and continued elimination of virtually all microglia from the CNS, without gross effects on peripheral macrophage populations. Mice lacking microglia, using this approach, are healthy, viable, and show no deleterious effects (we have treated for up to 3 months thus far). In CNS disease models we find that elimination of microglia is highly beneficial, suggesting that CSF1R antagonists could be an effective therapeutic for most CNS disorders. Crucially, CSF1R antagonists are in clinical trials for various cancers, and thus these findings are translatable. Our first aim is to track the fate of these eliminated microglia - do thy die with CSF1R inhibition, or do they dedifferentiate into a non-microglial cell? We have taken these findings further, to address the fundamental question of the regulation of microglia in the adult brain, by eliminating 99% of microglia via administration of CSF1R antagonists, and then withdrawing the antagonists to see if the microglia population could recover. Astonishingly, IBA-1 positive cells appear throughout the brain after just 3 days, with very different morphologies to resident microglia in control brains. These cells are also positive for CD45, nestin, Ki67 and stain with IB4. None of these markers are present in resident microglia in control brains. By 7 days, these cells have assumed similar morphologies to resident microglia, and these markers are absent once again. Thus, the adult brain has a highly plastic microglia population that can fully replenish itself when depleted, within days. Furthermore, we have identified a non- microglial cell that proliferates throughout the CNS and differentiates into the repopulating microglia - representing a potential microglia progenitor cell. This proposal seeks to further understand the origins of these "repopulating cells" and further characterize the transition of these potential microglia progenitor cells into microglia. In addition, we will look at the moleculr pathways that signal for repopulation of the microglia- depleted brain, and for differentiation int microglia, once present. Finally, we will assess the therapeutic potential of replacing "senescent" microglia in the aged brain with "repopulating" cells, and their ability to improve cognition and clear plaques in mouse models of Alzheimer's disease.

描述(申请人提供)：小胶质细胞与大多数中枢神经系统疾病有关，虽然它们在疾病方面起到保护作用，但它们的长期激活和存在会阻碍恢复，促进细胞损伤和认知能力下降。因此，抗炎策略一直被用作许多神经退行性疾病的潜在治疗药物，但缺乏效力。作为阿尔茨海默病发病机制中炎症研究的一部分，我们瞄准了集落刺激因子1受体(CSF1R)，因为它调节小胶质细胞的增殖。我们发现小胶质细胞实际上在生理上依赖于CSF1R信号，并且CSF1R拮抗剂的应用导致几乎所有的小胶质细胞迅速和持续地从 中枢神经系统，对外周巨噬细胞群无明显影响。使用这种方法，缺乏小胶质细胞的小鼠是健康的、存活的，并且没有显示出有害的影响(到目前为止，我们已经治疗了长达3个月)。在中枢神经系统疾病模型中，我们发现消除小胶质细胞是非常有益的，这表明CSF1R拮抗剂可能是治疗大多数中枢神经系统疾病的有效药物。至关重要的是，CSF1R拮抗剂正在对各种癌症进行临床试验，因此这些发现是可以翻译的。我们的第一个目标是追踪这些被消除的小胶质细胞的命运--你的死亡是CSF1R抑制，还是它们去分化为非小胶质细胞？我们进一步研究了这些发现，以解决成人大脑中小胶质细胞调节的根本问题，通过给予CSF1R拮抗剂消除99%的小胶质细胞，然后撤销拮抗剂，看看小胶质细胞数量是否可以恢复。令人惊讶的是，仅仅3天后，IBA-1阳性细胞就出现在整个大脑中，其形态与 对照组大脑中驻留的小胶质细胞。CD45、Nestin、Ki67阳性，IB4染色阳性。在对照组的大脑中，这些标志物都不存在于常驻的小胶质细胞中。到7天时，这些细胞已经呈现出与常驻小胶质细胞相似的形态，这些标志物再次缺失。因此，成人大脑中有一个高度可塑性的小胶质细胞群，在耗尽时，可以在几天内完全补充。此外，我们已经鉴定出一种非小胶质细胞，它可以在整个中枢神经系统中增殖，并分化为重新填充的小胶质细胞--代表了一个潜在的小胶质细胞前体细胞。这项提议寻求进一步了解这些“再繁殖细胞”的起源，并进一步表征这些潜在的小胶质细胞前体细胞向小胶质细胞的转变。此外，我们还将研究小胶质细胞枯竭的脑组织再生和小胶质细胞分化的分子信号通路。最后，我们将在阿尔茨海默病小鼠模型中，评估用“再生”细胞取代衰老大脑中“衰老”的小胶质细胞的治疗潜力，以及它们改善认知和清除斑块的能力。