Wei Ze-Xu, Xie Guo-Jun, Mao Xiao, Zou Xin-Peng, Liao Ya-Jin, Liu Qing-Shan, Wang Hua, Cheng Yong
Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, China.
The Third People's Hospital of Foshan, Foshan, Guangdong, China.
Neuropsychopharmacology. 2020 May;45(6):1050-1058. doi: 10.1038/s41386-020-0622-2. Epub 2020 Jan 27.
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.
外泌体微小RNA（miRNA）已被认为参与神经精神疾病的发病机制，但其在重度抑郁症（MDD）中的作用尚不清楚。我们对MDD患者和对照受试者血液来源的外泌体进行了全基因组miRNA表达谱分析，发现差异表达最显著的外泌体miRNA，即hsa-miR-139-5p（上调），在区分MDD患者和对照方面表现良好。将从MDD患者分离的血液外泌体经尾静脉注射到正常小鼠体内，通过强迫游泳、悬尾和新奇抑制摄食试验确定会导致其出现抑郁样行为，而将从健康志愿者分离的血液外泌体注射到经不可预测轻度应激（CUMS）处理的小鼠体内则可减轻其抑郁样行为。CUMS小鼠血液和大脑中外泌体miR-139-5p水平也显著升高。此外，经鼻注射miR-139-5p拮抗剂可挽救CUMS处理小鼠的抑郁样行为，这表明外泌体miR-139-5p水平升高可能介导小鼠应激诱导的抑郁样行为。外泌体治疗和miR-139-5p拮抗剂治疗均增加了CUMS处理小鼠的海马神经发生，而MDD患者外泌体处理则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，表明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，重度抑郁症患者的外泌体通过miR-139-5p调节的神经发生参与导致小鼠出现抑郁样行为。因此，外泌体miRNA是MDD诊断和治疗的有前景的靶点。
