PDF(Pubmed)
Abstract：
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons (MNs) in the brain and spinal cord, leading to progressive paralysis and death. Increasing evidence indicates that neuroinflammation plays an important role in ALS\'s pathogenesis and disease progression. Neuroinflammatory responses, primarily driven by activated microglia and astrocytes, and followed by infiltrating peripheral immune cells, contribute to exacerbate/accelerate MN death. In particular, the role of the microglia in ALS remains unclear, partly due to the lack of experimental models that can fully recapitulate the complexity of ALS\'s pathology. In this study, we developed and characterized a microglial cell line, SIM-A9-expressing human mutant protein Cu+/Zn+ superoxide dismutase_1 (SIM-A9hSOD1(G93A)), as a suitable model in vitro mimicking the microglia activity in ALS. The expression of hSOD1(G93A) in SIM-A9 cells induced a change in their metabolic activity, causing polarization into a pro-inflammatory phenotype and enhancing reactive oxygen species production, which is known to activate cell death processes and apoptosis. Afterward, we used our microglial model as an experimental set-up to investigate the therapeutic action of extracellular vesicles isolated from adipose mesenchymal stem cells (ASC-EVs). ASC-EVs represent a promising therapeutic treatment for ALS due to their neuroprotective and immunomodulatory properties. Here, we demonstrated that treatment with ASC-EVs is able to modulate activated ALS microglia, reducing their metabolic activity and polarizing their phenotype toward an anti-inflammatory one through a mechanism of reduction of reactive oxygen species.
摘要：
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是大脑和脊髓中上下运动神经元（MN）的进行性变性，导致进行性瘫痪和死亡。越来越多的证据表明,神经炎症在ALS的发病机制和疾病进展中起重要作用。神经炎症反应，主要由激活的小胶质细胞和星形胶质细胞驱动，然后浸润外周免疫细胞，有助于加重/加速MN死亡。特别是,小胶质细胞在ALS中的作用尚不清楚，部分原因是缺乏能够完全概括ALS病理学复杂性的实验模型。在这项研究中,我们开发并鉴定了一种小胶质细胞系，表达SIM-A9的人突变蛋白Cu/Zn超氧化物歧化酶_1（SIM-A9hSOD1（G93A）），作为体外模拟ALS中小胶质细胞活性的合适模型。hSOD1(G93A)在SIM-A9细胞中的表达诱导其代谢活性的改变,导致极化为促炎表型并增强活性氧的产生，已知激活细胞死亡过程和细胞凋亡。之后,我们使用我们的小胶质细胞模型作为实验装置来研究从脂肪间充质干细胞(ASC-EVs)分离的细胞外囊泡的治疗作用.ASC-EV由于其神经保护和免疫调节特性而代表了ALS的有希望的治疗性治疗。这里,我们证明，用ASC-EV治疗能够调节激活的ALS小胶质细胞，通过减少活性氧的机制，降低其代谢活性并使其表型朝着抗炎的方向发展。
