Defining the mechanisms of MSC extracellular vesicle modulation of microglia metabolism and bioenergetics in traumatic brain injury recovery

定义MSC细胞外囊泡调节小胶质细胞代谢和生物能学在创伤性脑损伤恢复中的机制

• 批准号: 10719905
• 负责人: Ross Marklein
• 金额: $ 50.93万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-08 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719905
• 关键词: Address; Affinity; Animals; Anxiety; Atrophic; Behavioral; Binding; Bioenergetics; Blood - brain barrier anatomy; Brain; Cells; Central Nervous System; Cerebrovascular Circulation; Cognition; Cognitive; Complex; Cues; Disease; Edema; Engineering; Environment; Event; Exhibits; Exploratory Behavior; Family suidae; Flow Cytometry; Functional disorder; Glycolysis; Hemorrhage; Histology; Immune; Immune System Diseases; Immune system; Immunohistochemistry; Immunotherapy; In Vitro; Individual; Infiltration; Inflammatory; Interferon Type II; Interleukin-6; Knowledge; Label; Lesion; Lung; Magnetic Resonance Imaging; Mediating; Memory; Metabolic; Metabolism; Microglia; Mitochondria; Modeling; Molecular; Morphology; Motor; Outcome; Oxidative Phosphorylation; Parents; Pathway interactions; Pattern; Pattern recognition receptor; Pericytes; Peripheral; Phenotype; Play; Population; Production; Proteomics; Reactive Oxygen Species; Regenerative Medicine; Role; Safety; Saline; Signal Transduction; Structure; Surface; Swelling; T-Lymphocyte; TBI treatment; TNF gene; Testing; Therapeutic; Thrombosis; Tight Junctions; Time; Traumatic Brain Injury; Traumatic Brain Injury recovery; Treatment Efficacy; Work; blood damage; blood-brain barrier crossing; cell injury; cell type; chemokine; cytokine; density; efficacy outcomes; extracellular vesicles; gait examination; immune cell infiltrate; immunomodulatory strategy; immunoregulation; improved; in vivo; intravenous administration; manufacture; mesenchymal stromal cell; metabolomics; monocyte; neuroinflammation; neuroprotection; neutrophil; novel; novel therapeutics; object recognition; preconditioning; regenerative therapy; response; social; success; tumorigenesis; uptake; white matter

PROJECT SUMMARY Neuroinflammation plays a critical role in both the onset and progression of traumatic brain injury (TBI); however, most therapies are unable to address the multifaceted aspects. Following TBI, microglia become activated and produce inflammatory cytokines (including TNF-α and IL-6) that damage blood brain barrier (BBB), tight junctions, and lead to infiltration of peripheral immune cells such as neutrophils, monocytes, and T cells. Identification of new immunomodulatory strategies that target microglia and promote a neuroprotective environment is critical for treating this devastating disease. Mesenchymal stromal cells (MSCs) are a promising therapy for regenerative medicine applications due to their immunomodulatory function, which is mediated by secreted extracellular vesicles (MSC-EVs) that possess distinct surface composition and intravesicular cargo. Our group has demonstrated the ability of MSC-EVs to modulate cell-types involved in neuroinflammation such as microglia, T cells and pericytes. MSC-EVs are a promising therapeutic for TBI because they can i) have comparable immunomodulatory function to parent MSCs, ii) cross the BBB, and iii) address safety concerns associated with MSC delivery (i.e. tumorigenesis and thrombosis). Further, the targeting capabilities (mediated by surface signals) and MSC-EV cargo can be engineered through priming (preconditioning) of MSCs with different microenvironmental cues such as cytokines Interferon-gamma and Tumor necrosis factor alpha. However, there is a gap in knowledge over the role and mechanisms of MSC-EV modulation of microglia in the context of TBI and whether this effect can be enhanced through priming. The proposed work seeks to elucidate the mechanisms by which MSC-EVs modulate microglia with a specific focus on MSC-EV mitochondrial transfer. Our central hypothesis is that MSC-EVs produced from cytokine-primed MSCs will have greater functionality through modulation of microglia towards a more neuroprotective phenotype (e.g. reduced production of inflammatory cytokines and reactive oxygen species) and that this effect is mediated by MSC-EV derived mitochondrial transfer in vitro and in vivo. We will test this hypothesis in the following aims: 1) Define the mechanisms of mitochondrial transfer from MSC-EV on microglia metabolism, and 2) Assess MSC-EV therapeutic efficacy in a porcine TBI model. Successful completion of the proposed work will create a novel, tunable approach for targeting the brain’s immune system and treating TBI through a better understanding of MSC-EV mechanisms of action.

项目摘要 神经炎症在创伤性脑损伤（TBI）的发作和进展中都起着至关重要的作用。 但是，大多数疗法无法解决多方面的方面。遵循TBI，小胶质细胞 被激活并产生损害血液的炎症细胞因子（包括TNF-α和IL-6） 脑屏障（BBB），紧密连接和导致外周免疫细胞（如 中性粒细胞，单核细胞和T细胞。识别针对目标的新免疫调节策略 小胶质细胞和促进神经保护环境对于治疗这种毁灭性疾病至关重要。 间充质基质细胞（MSC）是用于再生医学应用的有前途的疗法 其免疫调节功能是由分泌的细胞外蔬菜（MSC-EV）介导的 具有独特的表面组成和静脉内货物。我们的小组证明了 MSC-EVS调节参与神经炎症的细胞类型的能力，例如小胶质细胞，T细胞和 周细胞。 MSC-EVS是TBI的一种有希望的疗法，因为它们可以） 对父级的免疫调节功能，ii）越过BBB，iii）解决安全问题 与MSC递送有关（即肿瘤发生和血栓形成）。此外，目标功能 （由表面信号介导）和MSC-EV货物可以通过启动（预处理）进行设计 具有不同微环境线索的MSC，例如细胞因子干扰素γ和肿瘤 坏死因子α。但是，关于MSC-EV的作用和机制的知识存在差距 在TBI的背景下调节小胶质细胞，以及是否可以通过启动增强这种效果。 拟议的工作旨在阐明MSC-EVS通过A调节小胶质细胞的机制 对MSC-EV线粒体转移的特定关注。我们的中心假设是生产的MSC-EVS 从细胞因子培养的MSC中，通过调节小胶质细胞将具有更大的功能 更多的神经保护表型（例如，炎性细胞因子的产生和反应性降低 氧）并且这种作用是由MSC-EV衍生的线粒体转移在体外和 体内。我们将在以下目的中检验该假设：1）定义线粒体的机制 从小胶质细胞代谢上从MSC-EV转移，2）评估MSC-EV治疗效率 猪TBI模型。成功完成拟议的工作将创建一种新颖，可调的方法 用于针对大脑的免疫系统并通过更好地了解MSC-EV来治疗TBI 作用机理。