Role and Regulation of Neural Stem Cells in Remyelination

神经干细胞在髓鞘再生中的作用和调节

• 批准号: 10155591
• 负责人: JAMES SALZER
• 金额: $ 42.47万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155591
• 关键词: Ablation; Address; Adult; Area; Astrocytes; Axon; Brain; Cells; Chronic; Complement 1q; Complex; Corpus Callosum; Demyelinating Diseases; Demyelinations; Effectiveness; Future; Genetic; Genetic Enhancement; Goals; Inflammation; Inflammatory; Interneurons; Lesion; Maps; Mediator of activation protein; Microglia; Modeling; Morbidity - disease rate; Multiple Sclerosis; Myelin Sheath; Nerve Fibers; Neuroglia; Oligodendroglia; Pathologic; Patients; Pharmacology; Phenotype; Recovery; Recovery of Function; Research; Role; SHH gene; Secondary to; Series; Signal Transduction; Site; Source; Therapeutic; Transcript; cell type; improved; insight; nerve stem cell; nervous system disorder; neural recruitment; neuroregulation; novel; olfactory bulb; oligodendrocyte lineage; oligodendrocyte progenitor; precursor cell; prevent; recruit; remyelination; repaired; stem; stem cell expansion; stem cells; subventricular zone; therapy development; transcription factor; transcriptome sequencing; white matter

Project Summary Both oligodendrocyte progenitors (OPCs) and neural stem cells (NSCs) in the subventricular zone (SVZ) are known sources of remyelinating oligodendrocytes. Their precise contribution to remyelination and what limits their effectiveness in repair are active areas of research with important therapeutic implications. We have found that Sonic hedgehog (Shh)-responsive adult NSCs are a significant source of remyelinating cells. These NSCs, which are enriched in the ventral SVZ, normally give rise to parenchymal astrocytes and interneurons. They only enter white matter tracts upon demyelination, including to the the demyelinated corpus callosum (CC), where they are robustly recruited and differentiate preferentially into oligodendroglia. Unexpectedly, their recruitment to such lesions and their differentiation into remyelinating oligodendrocytes is significantly enhanced by genetic ablation or pharmacological inhibition of the Shh-dependent transcription factor Gli1. Further, pharmacological inhibition of Gli1 enhances remyelination in the adult and improves functional recovery from inflammatory demyelination. Important questions include whether their contribution to remyelination is impacted by competition with parenchymal OPCs during repair, what recruits these cells to demyelinated lesions, and how Gli1 limits NSC repair. In Aim 1, we examine whether NSCs expand their contribution to repair if OPC remyelination is blocked to assess whether NSC and OPCs compete to remyelinate the same lesion sites. In Aim 2, we assess the role of microglia (MG) and astrocytes, which are both activated in lesion sites, in the expansion and recruitment of NSCs. Our preliminary studies suggest MG are essential for NSC expansion and recruitment but do not indicate if this is a direct effect or is secondary to activation of astroglia. In Aim 3, we will investigate a novel NSC phenotype revealed by RNAseq that is only upregulated with demyelination and is Gli1- dependent. This phenotype includes a number of inflammation-related mediators and the C1q complex. We will characterize this altered NSC phenotype further, examine its potential role in regulating the number and phenotype of MG in the SVZ, and assess its potential impact on NSC clearance and remyelination. These studies will provide important, new insights into the signals (cells and molecules) that regulate the contribution of stem cells to repair and may thereby guide therapeutic efforts to promote remyelination.

项目摘要 室管膜下区（SVZ）的少突胶质细胞祖细胞（OPCs）和神经干细胞（NSCs） 是髓鞘再生少突胶质细胞的来源。它们对髓鞘再生的精确贡献， 限制它们在修复中的有效性的是具有重要治疗作用的活跃研究领域， 影响我们已经发现，Sonic hedgehog（Shh）反应性成体神经干细胞是一个重要的来源， 髓鞘再生细胞这些富集在腹侧SVZ中的NSC通常引起 实质星形胶质细胞和中间神经元。它们只在脱髓鞘时进入白色物质束， 包括脱髓鞘的胼胝体（CC），在那里它们被有力地招募， 优先分化成少突胶质细胞。出乎意料的是，他们的招募到这样的病变和他们的 向髓鞘再生少突胶质细胞的分化通过基因消融显著增强，或 Shh依赖性转录因子Gli1的药理学抑制。此外，药理学 抑制Gli1可增强成年人的髓鞘再生， 炎性脱髓鞘重要的问题包括它们对髓鞘再生的贡献是否 在修复过程中受到与实质OPCs竞争的影响，是什么招募这些细胞去脱髓鞘 损伤，以及Gli1如何限制NSC修复。在目标1中，我们研究了神经干细胞是否扩大了它们的贡献， 以评估NSC和OPCs是否竞争使神经元髓鞘再生， 相同的病变部位。在目标2中，我们评估了小胶质细胞（MG）和星形胶质细胞的作用，它们都是 在病变部位激活，在NSC的扩增和募集中。我们的初步研究表明MG 对NSC的扩展和招募至关重要，但没有说明这是直接影响还是 继发于星形胶质细胞的激活。在目标3中，我们将研究以下发现的一种新型NSC表型： RNAseq仅在脱髓鞘时上调，并且是Gli1依赖性的。该表型包括 炎症相关介质和C1q复合物的数量。我们将描述这个改变的国家安全委员会 表型进一步，检查其在调节SVZ中MG的数量和表型中的潜在作用， 并评估其对NSC清除和髓鞘再生的潜在影响。这些研究将提供 重要的是，对调节干细胞贡献的信号（细胞和分子）的新见解 从而指导治疗努力以促进髓鞘再生。