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.

项目总结