Sexually dimorphic extracellular vesicle responses after chronic spinal cord injury are associated with neuroinflammation and neurodegeneration in the aged brain.
Sexually dimorphic extracellular vesicle responses after chronic spinal cord injury are associated with neuroinflammation and neurodegeneration in the aged brain.
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DOI：
10.1186/s12974-023-02881-z
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发表时间：
2023-08-31
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
医学的进步使脊髓损伤(SCI)幸存者在遭受侮辱后存活数十年的可能性越来越大。但脊髓损伤如何影响衰老变化以及衰老对损伤过程的影响受到的关注有限。细胞外小泡(EVS)被认为是中枢神经系统损伤后神经炎症的关键介质，包括距离损伤部位较远的地方。我们先前已经证明，年轻雄性小鼠的脊髓损伤导致血浆EV计数和microRNA(MiR)含量的强烈变化。在这里，我们的目标是研究生物学性别和衰老对脊髓损伤后EVS和脑的影响。将年龄匹配的幼年C57BL/6雄性和雌性小鼠进行脊髓损伤。伤后19个月，超速离心法分离血浆总EV，并用纳米颗粒示踪分析(NTA)进行表征。EVS miR货物用Fiplex®检测。脑内转录的变化由纳米串神经病理小组评估，并通过Western印迹(WB)和流式细胞术(FC)进行验证。进行了一系列行为测试，以评估神经功能。转录改变显示假手术组和脊髓损伤组之间有大量的改变。在与疾病关联、激活的小胶质细胞和囊泡运输相关的转录网络中发现了性别特异性的变化。Fc组大鼠脊髓损伤组织中的小胶质细胞和髓样细胞数高于男性，损伤部位和脑组织中的ROS含量也高于男性。在后者中，脊髓损伤/雌性小胶质细胞的肿瘤坏死因子水平和线粒体膜电位升高。WB和NTA显示脊髓损伤/男性患者血浆中EV标志物水平升高。损伤后大脑皮质颗粒浓度升高，脊髓损伤/雌性比脊髓损伤/雄性更多。EVS货物分析显示，miR含量的变化与伤害和性别有关。行为学测试证实，在脊髓损伤后的慢性时间点，男女患者均存在认知障碍和抑郁，男女之间无显著差异。我们的研究首次显示了很长时间的脊髓损伤后脑性二形性改变，并支持一种潜在的性别依赖的EV介导的机制，有助于脊髓损伤诱导的脑改变。网上版载有补充材料，可在10.1186/s12974-023-02881-z查阅。
Medical advances have made it increasingly possible for spinal cord injury (SCI) survivors to survive decades after the insult. But how SCI affects aging changes and aging impacts the injury process have received limited attention. Extracellular vesicles (EVs) are recognized as critical mediators of neuroinflammation after CNS injury, including at a distance from the lesion site. We have previously shown that SCI in young male mice leads to robust changes in plasma EV count and microRNA (miR) content. Here, our goal was to investigate the impact of biological sex and aging on EVs and brain after SCI. Young adult age-matched male and female C57BL/6 mice were subjected to SCI. At 19 months post-injury, total plasma EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis (NTA). EVs miR cargo was examined using the Fireplex® assay. The transcriptional changes in the brain were assessed by a NanoString nCounter Neuropathology panel and validated by Western blot (WB) and flow cytometry (FC). A battery of behavioral tests was performed for assessment of neurological function. Transcriptomic changes showed a high number of changes between sham and those with SCI. Sex-specific changes were found in transcription networks related to disease association, activated microglia, and vesicle trafficking. FC showed higher microglia and myeloid counts in the injured tissue of SCI/Female compared to their male counterparts, along with higher microglial production of ROS in both injured site and the brain. In the latter, increased levels of TNF and mitochondrial membrane potential were seen in microglia from SCI/Female. WB and NTA revealed that EV markers are elevated in the plasma of SCI/Male. Particle concentration in the cortex increased after injury, with SCI/Female showing higher counts than SCI/Male. EVs cargo analysis revealed changes in miR content related to injury and sex. Behavioral testing confirmed impairment of cognition and depression at chronic time points after SCI in both sexes, without significant differences between males and females. Our study is the first to show sexually dimorphic changes in brain after very long-term SCI and supports a potential sex-dependent EV-mediated mechanism that contributes to SCI-induced brain changes. The online version contains supplementary material available at 10.1186/s12974-023-02881-z.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
29
作者：
Davis EJ;Solsberg CW;White CC;Miñones-Moyano E;Sirota M;Chibnik L;Bennett DA;De Jager PL;Yokoyama JS;Dubal DB
通讯作者：
Dubal DB
影响因子：
8.8
作者：
Inquimbert P;Moll M;Latremoliere A;Tong CK;Whang J;Sheehan GF;Smith BM;Korb E;Athié MCP;Babaniyi O;Ghasemlou N;Yanagawa Y;Allis CD;Hof PR;Scholz J
通讯作者：
Scholz J
影响因子：
9.2
作者：
Garry, EM;Moss, A;Fleetwood-Walker, SM
通讯作者：
Fleetwood-Walker, SM
影响因子：
9.6
作者：
DEVIVO, MJ;IVIE, CS
通讯作者：
IVIE, CS