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.

项目概要 神经炎症在创伤性脑损伤 (TBI) 的发生和进展中起着至关重要的作用； 然而，大多数疗法无法解决 TBI 后的多方面问题。 被激活并产生损伤血液的炎性细胞因子（包括 TNF-α 和 IL-6） 脑屏障（BBB）、紧密连接，并导致外周免疫细胞的浸润，例如 鉴定针对中性粒细胞、单核细胞和 T 细胞的新免疫调节策略。 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）是再生医学应用的一种有前途的疗法，因为 其免疫调节功能由分泌性细胞外囊泡 (MSC-EV) 介导 我们的团队已经证明了具有独特的表面成分和囊泡内货物的物质。 MSC-EV 调节参与神经炎症的细胞类型（例如小胶质细胞、T 细胞和 MSC-EV 是一种很有前景的 TBI 治疗方法，因为它们 i) 具有可比性。 对亲代 MSC 的免疫调节功能，ii) 穿过 BBB，以及 iii) 解决安全问题 与 MSC 递送（即肿瘤发生和血栓形成）相关。 （由表面信号介导）和 MSC-EV 货物可以通过启动（预处理）进行改造 具有不同微环境线索（例如细胞因子、干扰素-γ和肿瘤）的 MSC 然而，对于 MSC-EV 的作用和机制的了解还存在空白。 TBI 背景下小胶质细胞的调节以及这种效应是否可以通过启动增强。 拟议的工作旨在阐明 MSC-EV 通过以下方式调节小胶质细胞的机制： 我们特别关注 MSC-EV 线粒体转移。我们的中心假设是 MSC-EV 产生。 细胞因子引发的间充质干细胞将通过调节小胶质细胞而具有更大的功能 更多的神经保护表型（例如减少炎症细胞因子和反应性细胞因子的产生） 氧物种），并且这种效应是由 MSC-EV 衍生的体外线粒体转移介导的 我们将在体内测试这一假设：1）定义线粒体的机制。 MSC-EV 对小胶质细胞代谢的转移，以及 2) 评估 MSC-EV 的治疗效果 猪 TBI 模型的成功完成将创建一种新颖的、可调节的方法。 通过更好地了解 MSC-EV 来瞄准大脑的免疫系统并治疗 TBI 行动机制。