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

基本信息

批准号：
10412936
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
项目类别：
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/10412936
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

项目摘要

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.

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Activated microglia drive demyelination via CSF1R signaling.

DOI：
10.1002/glia.23980
发表时间：
2021-06
期刊：
Glia
影响因子：
6.2
作者：
通讯作者：

Relative Levels of Gli1 and Gli2 Determine the Response of Ventral Neural Stem Cells to Demyelination.

DOI：
10.1016/j.stemcr.2020.10.003
发表时间：
2020-11-10
期刊：
Stem cell reports
影响因子：
5.9
作者：
Radecki DZ;Messling HM;Haggerty-Skeans JR;Bhamidipati SK;Clawson ED;Overman CA;Thatcher MM;Salzer JL;Samanta J
通讯作者：
Samanta J

Transcriptomic analysis of loss of Gli1 in neural stem cells responding to demyelination in the mouse brain.