hUC-MSCs ameliorated CUMS-induced depression by modulating complement C3 signaling-mediated microglial polarization during astrocyte-microglia crosstalk.,Brain Research Bulletin

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hUC-MSCs ameliorated CUMS-induced depression by modulating complement C3 signaling-mediated microglial polarization during astrocyte-microglia crosstalk.
Brain Research Bulletin ( IF 3.5 ) Pub Date : 2020-07-15 , DOI: 10.1016/j.brainresbull.2020.07.004
Jing Li ₁ , Hualong Wang ₁ , Chongbo Du ₁ , Xiaojing Jin ₁ , Yuan Geng ₁ , Bing Han ₁ , Qinying Ma ₁ , Quanhai Li ₂ , Qian Wang ₃ , Yidi Guo ₃ , Mingwei Wang ₁ , Baoyong Yan ₄

Affiliation

Background

Major depressive disorder (MDD) has been shown to be related to immune inflammation and the complement system. Previous studies have suggested that human umbilical cord mesenchymal stem cells (hUC-MSCs) play an important role in inflammatory diseases.

Methods

hUC-MSCs were administered into chronic unpredictable mild stress model (CUMS) mice through the tail vein once a week for 4 weeks. After the administration of hUC-MSCs, the depression-like and anxiety-like phenotypes, neuronal histopathology, synaptic-related protein expression and inflammatory index of the mice were assessed. Microglial M1/M2 polarization and the expression of C3a in astrocytes and C3aR in microglia was detected by immunofluorescence co-localization. Then, CUMS mice were injected with a C3aR antagonist, and the expression of C3a and C3aR and microglial polarization were observed.

Results

Based on the sucrose preference and tail suspension tests, hUC-MSCs ameliorated the depression-like behaviors of CUMS mice. Additionally, the anxiety-like behaviors of CUMS mice in the open-field and plus-maze tests were improved after the administration of hUC-MSCs. hUC-MSCs altered microglia polarization by alleviating complement C3a-C3aR signaling activation, which decreased pro-inflammatory factor levels and increased anti-inflammatory factor levels, alleviating neuronal damage and synaptic deficits.

Conclusion

hUC-MSCs have therapeutic effects on anxiety-like and depressive-like phenotypes caused by CUMS. They can alter the polarization of microglia by inhibiting C3a-C3aR signaling to reduce neuroinflammation.

中文翻译：

hUC-MSCs 通过在星形胶质细胞-小胶质细胞串扰期间调节补体 C3 信号介导的小胶质细胞极化来改善 CUMS 诱导的抑郁症。

背景

重度抑郁症 (MDD) 已被证明与免疫炎症和补体系统有关。先前的研究表明，人脐带间充质干细胞 (hUC-MSCs) 在炎症性疾病中发挥重要作用。

方法

hUC-MSCs 每周一次通过尾静脉注射到慢性不可预测轻度应激模型 (CUMS) 小鼠中，持续 4 周。hUC-MSCs给药后，评估小鼠的抑郁样和焦虑样表型、神经元组织病理学、突触相关蛋白表达和炎症指数。通过免疫荧光共定位检测小胶质细胞 M1/M2 极化和星形胶质细胞中 C3a 和小胶质细胞中 C3aR 的表达。然后，给CUMS小鼠注射C3aR拮抗剂，观察C3a和C3aR的表达及小胶质细胞极化。

结果

基于蔗糖偏好和悬尾试验，hUC-MSCs 改善了 CUMS 小鼠的抑郁样行为。此外，在施用 hUC-MSCs 后，CUMS 小鼠在开放场和十字迷宫试验中的焦虑样行为得到改善。hUC-MSCs 通过减轻补体 C3a-C3aR 信号激活来改变小胶质细胞极化，从而降低促炎因子水平和增加抗炎因子水平，减轻神经元损伤和突触缺陷。