Mechanisms underlying extracellular vesicle mediated changes in inflammation, neural circuitry and plasticity following cortical injury in aged monkeys

细胞外囊泡介导老年猴子皮质损伤后炎症、神经回路和可塑性变化的机制

• 批准号: 10664001
• 负责人: TARA L MOORE
• 金额: $ 64.18万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664001
• 关键词: Acceleration; Acute; Alzheimer' s disease related dementia; Anti-Inflammatory Agents; Area; Astrocytes; Attention; Automobile Driving; Axon; Behavioral; Biological Markers; Blood; Brain; Cell Survival; Cells; Chronic; Cognitive deficits; Craniocerebral Trauma; Development; Dimensions; Early treatment; Encapsulated; Environment; Exhibits; FDA approved; FOS gene; Female; Glucose; Hand; Harvest; Histologic; Hour; Human; Immediate-Early Genes; Immune signaling; In Vitro; Inflammation; Inflammatory; Injury; Intravenous; Investigation; Knowledge acquisition; Label; Lesion; Macaca mulatta; Magnetic Resonance Imaging; Maps; Measures; Mediating; Mesenchymal Stem Cells; MicroRNAs; Microglia; Microscopy; Molecular; Molecular Mechanisms of Action; Monkeys; Motor; Motor Cortex; Myelin; Nature; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuroglia; Neuronal Plasticity; Neurons; Oligodendroglia; Oxidative Stress; Oxygen; Phenotype; Physiological; Physiology; Postoperative Period; Process; Proteins; Proteomics; Recovery; Recovery Support; Recovery of Function; Resolution; Signaling Protein; Stroke; Synapses; Testing; Therapeutic; Time; Tissue Harvesting; Tracer; Training; Validation; Work; age related; aged; aging brain; anatomical tracer; behavioral outcome; brain cell; brain tissue; cell injury; cell type; cohort; deprivation; excitotoxicity; extracellular vesicles; hand dysfunction; in vitro Model; in vivo; inflammatory marker; injury recovery; male; mesenchymal stromal cell; motor deficit; motor function recovery; multidisciplinary; multimodality; myelination; neural; neural circuit; neuroinflammation; neuronal excitability; neuroprotection; oxidative damage; patch clamp; remyelination; repaired; response; response to injury; sex; single nucleus RNA-sequencing; single-cell RNA sequencing; tissue repair; transcriptomics; Acceleration; Acute; Alzheimer' s disease related dementia; Anti-Inflammatory Agents; Area; Astrocytes; Attention; Automobile Driving; Axon; Behavioral; Biological Markers; Blood; Brain; Cell Survival; Cells; Chronic; Cognitive deficits; Craniocerebral Trauma; Development; Dimensions; Early treatment; Encapsulated; Environment; Exhibits; FDA approved; FOS gene; Female; Glucose; Hand; Harvest; Histologic; Hour; Human; Immediate-Early Genes; Immune signaling; In Vitro; Inflammation; Inflammatory; Injury; Intravenous; Investigation; Knowledge acquisition; Label; Lesion; Macaca mulatta; Magnetic Resonance Imaging; Maps; Measures; Mediating; Mesenchymal Stem Cells; MicroRNAs; Microglia; Microscopy; Molecular; Molecular Mechanisms of Action; Monkeys; Motor; Motor Cortex; Myelin; Nature; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuroglia; Neuronal Plasticity; Neurons; Oligodendroglia; Oxidative Stress; Oxygen; Phenotype; Physiological; Physiology; Postoperative Period; Process; Proteins; Proteomics; Recovery; Recovery Support; Recovery of Function; Resolution; Signaling Protein; Stroke; Synapses; Testing; Therapeutic; Time; Tissue Harvesting; Tracer; Training; Validation; Work; age related; aged; aging brain; anatomical tracer; behavioral outcome; brain cell; brain tissue; cell injury; cell type; cohort; deprivation; excitotoxicity; extracellular vesicles; hand dysfunction; in vitro Model; in vivo; inflammatory marker; injury recovery; male; mesenchymal stromal cell; motor deficit; motor function recovery; multidisciplinary; multimodality; myelination; neural; neural circuit; neuroinflammation; neuronal excitability; neuroprotection; oxidative damage; patch clamp; remyelination; repaired; response; response to injury; sex; single nucleus RNA-sequencing; single-cell RNA sequencing; tissue repair; transcriptomics

Abstract Changes in the aged brain that occur with stroke, head injury or Alzheimer’s Disease Related Dementias (ADRD) result in chronic cognitive and motor deficits. Mesenchymal stem cells (MSCs) have recently received attention to reverse or slow neurodegenerative and injury-related changes in the aging brain as they suppress inflammation and facilitate tissue repair and remyelination. We have now completed studies as part of R21- NS102991 and R56-NS112207 that have shown that MSC-derived extracellular vesicles (EVs), the active product of MSCs, accelerate and enhance recovery of motor function following cortical injury in aged female monkeys. EV-treated monkeys exhibited full recovery by 3-5 weeks post-injury and untreated monkeys reached a plateau in recovery by 8-12 weeks post-injury. At a chronic recovery stage (16-weeks post-injury, R21- NS102991), MSC-EVs reduced injury-induced microglial neuroinflammation, neuronal excitotoxicity, synapse loss, oligodendrocyte damage and myelination deficits. However, the precise nature of how MSC-EVs act within both acute or chronic stages of recovery after injury remains unknown and is important to decipher in order to fine tune the efficacious use of MSC-EVs for age-related injury and neurodegenerative diseases. Our preliminary analysis of injury- and MSC-EV-associated changes in blood and brain tissue collected at an earlier stage of recovery (6 weeks post-injury, R56-NS112207) showed early treatment-related differences in microglial phenotypes and neuronal excitability that are distinct from treatment-related differences observed at 16-week post-injury. Therefore, we now propose to continue and expand these studies to combine in vivo behavioral, MRI and proteomic CSF and blood biomarker analyses with comprehensive proteomic and single-cell transcriptomic profiling and physiological and histological assessments of brain tissue harvested at distinct time points during recovery (3, 6, 9 weeks post- injury) from male and females aged monkeys. Furthermore, using advance human- derived in-vitro models, we will elucidate specific encapsulated miRNAs or/and proteins of MSC-EVs that ameliorate injury-related inflammatory and oxidative responses, and facilitate recovery and neuroprotection. We hypothesize that MSC-EVs contain miRNA and protein signals that modulate the acute response to injury and mitigate immediate damage, leading to reduced secondary chronic inflammation and degeneration, promoting a restorative microenvironment that will facilitate neural plasticity later in recovery. These studies will elucidate the temporal progression, sex-dependent dynamics and cell-specific molecular mechanism(s) of action of MSC-EV mediated recovery, that will pave the way for its potential development as a therapeutic for age-related injury and neurodegenerative diseases in humans.

抽象的 中风，头部损伤或阿尔茨海默氏病与痴呆症相关的衰老大脑的变化（ADRD） 导致慢性认知和运动防御能力。间充质干细胞（MSC）最近受到关注 逆转或减慢神经退行性和损伤相关的衰老大脑的变化 炎症并促进组织修复和透明。现在，我们已经完成研究，作为R21-的一部分 NS102991和R56-NS112207表明MSC衍生的细胞外蔬菜（EV），活动性 MSC的产物，老年女性皮质损伤后运动功能的加速和增强恢复 猴子。经过EV处理的猴子在伤害后3-5周暴露了完全恢复，未经治疗的猴子到达了 伤害后8-12周的恢复高原。在慢性恢复阶段（16周伤害后，R21-- NS102991），MSC-EV降低了损伤诱导的小胶质细胞神经炎症，神经兴奋性，突触 损失，少突胶质细胞损伤和髓鞘化定义。但是，MSC-EV在其中的确切性质 受伤后的急性或慢性恢复阶段尚不清楚，对破译至关重要 微调MSC-EV在与年龄相关的损伤和神经退行性疾病中的有效使用。我们的初步 分析在早期阶段收集的血液和脑组织的损伤和MSC与MSC相关的变化 恢复（伤害后6周，R56-NS112207）显示了与治疗相关的小胶质细胞的差异 表型和神经元的刺激性与在16周时观察到的与治疗相关的差异不同 伤害后。因此，我们现在建议继续并扩展这些研究，以结合体内行为，MRI 蛋白质组学CSF和血液生物标志物分析具有全面的蛋白质组学和单细胞转录组。 在不同时间点收获的脑组织的分析以及物理和组织学评估 从男性和女性老化的猴子中恢复（3、6、9周）。此外，使用先进的人类 派生的体内模型，我们将阐明MSC-EV的特定封装miRNA或/和/和/和蛋白质 改善与损伤相关的炎症和氧化反应，并促进恢复和神经保护。我们 假设MSC-EVs包含miRNA和蛋白质信号，这些信号调节了对损伤的急性反应和 减轻立即损害，导致继发性慢性感染和变性减少，促进 恢复性微环境将促进恢复后的神经可塑性。这些研究将阐明 MSC-EV的作用的暂时进展，性依赖性动力学和细胞特异性分子机制 介导的恢复，这将为其作为与年龄相关的伤害的治疗性的潜在发展铺平道路 和人类的神经退行性疾病。