Neural Stem Cell – Derived small Extracellular Vesicles Ameliorate the Disease Progression in SOD1 G93A Murine Model

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons, leading to muscle weakness, paralysis, and ultimately, respiratory failure. Extracellular vesicles (EVs) facilitate intercellular communication by mimicking the functions of their parent cells. In this study, we confirmed that repeated administration of neural stem cell - derived small extracellular vesicles (NSC-derived sEVs) improved motor performance and provided protection to lumbar motor neurons, the neuromuscular junctions, and muscle morphology in the SOD1 G93A transgenic mouse model. Furthermore, by analyzing the miRNA profiles of NSC-derived EVs and RNA-sequencing of muscle specimens from ALS-SOD1 patients, we demonstrated the rescue effects of NSC- derived EVs might be linked to the p53 pathway. Compared to the PBS group, both TP53 and the p53 upregulated modulator of apoptosis (puma) were downregulated in the spinal cord of mice treated with NSC-derived EVs. These data contribute by providing additional knowledge for the promising use of NSC-derived EVs as a potential therapy for ALS.肌萎缩侧索硬化症（Amyotrophic lateral sclerosis, ALS）是一种进行性神经退行性疾病，主要累及运动神经元，可导致肌肉无力、瘫痪，最终引发呼吸衰竭。细胞外囊泡（extracellular vesicles, EVs）可通过模拟亲本细胞的功能介导细胞间通讯。本研究证实，反复给予神经干细胞源性小细胞外囊泡（neural stem cell-derived small extracellular vesicles, NSC-derived sEVs）可改善SOD1 G93A转基因小鼠模型的运动功能，并对腰椎运动神经元、神经肌肉接头及肌肉形态起到保护作用。此外，通过分析NSC源性EVs的miRNA表达谱以及ALS-SOD1患者肌肉标本的RNA测序数据，本研究发现NSC源性EVs的保护效应可能与p53通路相关。与PBS组相比，接受NSC源性sEVs治疗的小鼠脊髓中，TP53及p53上调凋亡调控因子（p53 upregulated modulator of apoptosis, PUMA）的表达均出现下调。本研究数据为NSC源性sEVs作为ALS潜在治疗手段的应用前景提供了新增的科学依据。