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Meningeal Stem Cell Signals for Improving Sensorimotor and Cognitive Outcomes After Stroke

脑膜干细胞信号可改善中风后的感觉运动和认知结果

基本信息

批准号：
10528477
负责人：
Kazuhide Hayakawa
金额：
$ 39.21万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10528477
关键词：
AMD3100 Accounting Animal Model Astrocytes BMP2 gene Behavior assessment Blood - brain barrier anatomy Blood Vessels Brain Brain Injuries Brain-Derived Neurotrophic Factor CD 200 CRISPR/Cas technology CXCR CXCR4 gene Cell Communication Cell Culture Techniques Cell Death Cells Cerebral Ischemia Cerebral cortex Coculture Techniques Cognitive Collaborations Cre lox recombination system Data Defect Development Endothelium Female Genes Goals Growth Factor HDAC3 gene Human Infarction Injury Ischemia Label Literature Location Macrophage Maps Mediating Mediator Membrane Meningeal Meninges Methods Modeling Modification Molecular Multipotent Stem Cells Mus Neuroglia Neuronal Injury Neurons Outcome Pathway interactions Patients Pericytes Process Publishing Radial Rattus Recovery Signal Transduction Source Stroke Stromal Cell-Derived Factor 1 Testing Therapeutic Transforming Growth Factor beta Up-Regulation Western Blotting activin A behavior test blood damage brain endothelial cell cognitive recovery endothelial repair experimental study functional outcomes gain of function improved in vivo in vivo Model in vivo imaging inhibitor loss of function male migration mortality mouse model neural neurogenesis neurological recovery neurovascular neurovascular unit neutralizing antibody new therapeutic target novel novel strategies optical imaging pharmacologic post stroke post stroke dementia receptor repaired response restoration spatiotemporal stem cell migration stem cell niche stem cell proliferation stem cells stroke cognitive outcome stroke recovery therapeutic target tool

项目摘要

Meningeal stem cell signals for improving sensorimotor and cognitive outcomes after stroke Mortality after stroke has decreased. The challenge now is how to deal with the accumulating burden of sensorimotor deficits and post-stroke dementia in surviving patients. In this proposal, we will investigate the meninges as a novel source of stem cell signals that may potentially assist with neurovascular unit recovery. Our pilot data suggest that: (i) meningeal multipotent stem cells (MeSCs) migrate to perivascular space after focal ischemia, (ii) MeSC response may be significant, accounting for up to 30% of CD271 “total stem cell response”, (iii) this is an “active process” since inhibiting CXCR4 decreased MeSC migration, (iv) MeSC response may be a relevant therapeutic target since it can be significantly amplified by blocking CD271- mediated stem cell death with LM11A-31, whereas blocking SDF-1 signaling with AMD3100 decreased MeSC migration and worsened blood-brain barrier (BBB) injury; (v) beneficial actions of MeSC may involve restoration of vascular integrity and upregulation of TGF-β-stimulated macrophages that further promote neurogenic responses, and finally (vi) models and methods to dissect this phenomenon are feasible including molecular tools, vasculome mapping, behavioral tests, and in vivo imaging in our collaborating labs. Based on our pilot data, we hypothesize that (a) brain endothelial cells and astrocytes secrete SDF-1 into perivascular space to attract MeSCs, (b) MeSCs restore damaged BBB and rescue the vasculome, (c) MeSC crosstalk with perivascular macrophages promotes TGF-β-mediated neurogenesis, and (d) MeSC-mediated neurovascular unit recovery ameliorates sensorimotor deficits and post-stroke dementia. We have 3 specific aims. In Aim 1, we will map the profile of MeSC proliferation, accumulation, and differentiation in focal cerebral ischemia. In Aim 2, we will investigate cellular mechanisms of crosstalk between MeSCs and vascular/perivascular cells that underlie MeSC migration, BBB repair, vasculome renormalization and neurogenesis. In Aim 3, we will use gain and loss-of-function experiments to modify MeSC-mediated neurovascular remodeling, and assess sensorimotor and cognitive outcomes in vivo. Our experiments will utilize cell cultures and animal models. Molecular tools include a combination of pharmacologic activators/inhibitors, CRISPR/cas9, and cre-lox systems to modify specific pathways and genes. Translational relevance will be assessed with in vivo imaging and long-term outcomes. This project should define a novel mechanism wherein meningeal stem cells communicate with the neurovascular unit, and hopefully provide new approaches to improve sensorimotor recovery and ameliorate post-stroke dementia.

脑膜干细胞信号改善中风后感觉运动和认知预后