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: 10501439
• 负责人: TARA L MOORE
• 金额: $ 68.05万
• 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/10501439
• 关键词: Acute; Alzheimer' s disease related dementia; Anti-Inflammatory Agents; Area; Astrocytes; Attention; Automobile Driving; Axon; Behavioral; Biological Markers; Blood; Brain; Cell Nucleus; Cell Survival; Cells; Chronic; Cognitive deficits; Craniocerebral Trauma; Development; 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; 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 tracing; behavioral outcome; brain cell; brain magnetic resonance imaging; 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 circuit; neuroinflammation; neuronal excitability; neuroprotection; oxidative damage; patch clamp; relating to nervous system; remyelination; repaired; response; response to injury; sex; single-cell RNA sequencing; tissue repair; transcriptome sequencing; 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、头部受伤或阿尔茨海默病相关痴呆症 (ADRD) 导致的老年大脑变化 导致慢性认知和运动缺陷的间充质干细胞（MSC）最近受到关注。 逆转或减缓衰老大脑中神经退行性和损伤相关的变化，因为它们抑制 炎症并促进组织修复和髓鞘再生，作为 R21- 的一部分，我们现已完成研究。 NS102991 和 R56-NS112207 已表明 MSC 衍生的细胞外囊泡 (EV) MSCs产物，加速和增强老年女性皮质损伤后运动功能的恢复 接受 EV 治疗的猴子在受伤后 3-5 周内表现出完全康复，而未经治疗的猴子则达到了完全恢复。 受伤后 8-12 周恢复平稳 处于慢性恢复阶段（受伤后 16 周，R21-） NS102991)，MSC-EV 减少损伤引起的小胶质细胞神经炎症、神经元兴奋性毒性、突触 然而，MSC-EV 的作用的确切性质。 受伤后的急性或慢性恢复阶段仍然未知，破译这一点很重要，以便 我们的初步研究对 MSC-EV 的有效使用进行了微调，以治疗与年龄相关的损伤和神经退行性疾病。 分析早期阶段收集的血液和脑组织中与损伤和 MSC-EV 相关的变化 恢复（受伤后 6 周，R56-NS112207）显示小胶质细胞的早期治疗相关差异 表型和神经兴奋性与 16 周时观察到的治疗相关差异不同 因此，我们现在建议继续并扩大这些研究，将体内行为、MRI 结合起来。 以及蛋白质组脑脊液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学 对在不同时间点采集的脑组织进行分析以及生理和组织学评估 雄性和雌性老年猴子的恢复（受伤后 3、6、9 周）此外，使用先进的人类模型。 衍生的体外模型，我们将阐明 MSC-EV 的特定封装 miRNA 或/和蛋白质 改善损伤相关的炎症和氧化反应，并促进恢复和神经保护。 MSC-EV 含有 miRNA 和蛋白质信号，可调节对损伤的急性反应 减轻直接损害，从而减少继发性慢性炎症和变性，促进 这些研究将阐明恢复后的神经可塑性。 MSC-EV 的时间进程、性别依赖性动力学和细胞特异性分子机制 介导的恢复，这将为它作为年龄相关损伤治疗的潜在发展铺平道路 和人类神经退行性疾病。