Exosomal microRNAs (miRNAs) have been suggested to participate in the pathogenesis of neuropsychiatric diseases, but their role in major depressive disorder (MDD) is unknown. We performed a genome-wide miRNA expression profiling of blood-derived exosomes from MDD patients and control subjects and revealed the top differentially expressed exosomal miRNA, i.e. hsa-miR-139-5p (upregulation), had good performance to differentiate between MDD patients and controls. Tail vein injection of blood exosomes isolated from MDD patients into normal mice caused their depressive-like behaviors as determined by the forced swimming, tail suspension, and novelty suppressed feeding tests, and injection of blood exosomes isolated from healthy volunteers into unpredictable mild stress (CUMS)-treated mice alleviated their depressive-like behaviors. CUMS mice also showed significantly increased blood and brain levels of exosomal miR-139-5p. Furthermore, the depressive-like behaviors in CUMS-treated mice were rescued by intranasal injection of miR-139-5p antagomir, suggesting that increased exosomal miR-139-5p levels may mediate stress-induced depression-like behavior in mice. Both exosome treatment and miR-139-5p antagomir treatment increased hippocampal neurogenesis in the CUMS-treated mice, and treatment of exosome from MDD patients decreased hippocampal neurogenesis in the normal mice. The role of miR-139-5p in neurogenesis was validated by in vitro experiments, demonstrating that miR-139-5p is a negative regulator for neural stem cell proliferation and neuronal differentiation. Our findings together suggest that exosomes from patients with major depression caused depressive-like behaviors in mice with involvement of miR-139-5p-regulated neurogenesis. Therefore, exosomal miRNAs are promising targets for the diagnosis and treatment of MDD.

中文翻译：

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来自重度抑郁症患者的外泌体导致小鼠出现抑郁样行为，并涉及 miR-139-5p 调节的神经发生。

外泌体 microRNA (miRNA) 被认为参与了神经精神疾病的发病机制，但它们在重度抑郁症 (MDD) 中的作用尚不清楚。我们对来自 MDD 患者和对照受试者的血液来源的外泌体进行了全基因组 miRNA 表达谱分析，并揭示了最高差异表达的外泌体 miRNA，即 hsa-miR-139-5p（上调），在区分 MDD 患者和控制。将 MDD 患者分离的血液外泌体尾静脉注射到正常小鼠体内会导致它们的抑郁样行为，这由强制游泳、悬尾和新奇抑制喂养试验以及将健康志愿者分离的血液外泌体注射到不可预测的轻度压力 (CUMS) 中确定。 ) 治疗的小鼠减轻了他们的抑郁样行为。CUMS 小鼠的血液和大脑外泌体 miR-139-5p 水平也显着增加。此外，通过鼻内注射 miR-139-5p antagomir 挽救了 CUMS 治疗小鼠的抑郁样行为，这表明增加的外泌体 miR-139-5p 水平可能介导应激诱导的小鼠抑郁样行为。外泌体治疗和 miR-139-5p antagomir 治疗均增加了 CUMS 治疗小鼠的海马神经发生，而治疗 MDD 患者的外泌体降低了正常小鼠的海马神经发生。体外实验验证了 miR-139-5p 在神经发生中的作用，证明 miR-139-5p 是神经干细胞增殖和神经元分化的负调节因子。我们的研究结果共同表明，来自重度抑郁症患者的外泌体在涉及 miR-139-5p 调节的神经发生的小鼠中引起抑郁样行为。因此，外泌体 miRNA 是 MDD 诊断和治疗的有希望的靶点。