Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44# Wenhua Xi Road, Jinan, Shandong, 250012, PR China.
Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, PR China.
Pharmacol Res. 2021 Feb;164:105322. doi: 10.1016/j.phrs.2020.105322. Epub 2020 Dec 3.
Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) significantly suppressed hypoxia-ischemia (HI)-induced neuroinflammation in neonatal mice. However, its underlying mechanism is still unknown. Osteopontin (OPN) is one of the key molecules involved in neuroinflammation. We demonstrate here for the first time a key role of OPN in EVs-mediated neuroinflammation following HI. Firstly, HI exposure upregulated OPN expression in Iba-1/ TMEM119 microglia and Iba-1/TMEM119 monocytes/macrophages. Blocking OPN mRNA expression with LV-shOPN attenuated edema, infarct volumes, and the levels of inflammatory cytokines following HI exposure. MSCs-EVs treatment remarkably restored synaptic reorganization and up-regulated synaptic protein expression post-HI, concomitant with reducing OPN levels. Moreover, MSCs-EVs treatment rescued microglial phagocytosis of viable neurons following HI, concomitant with decreasing OPN expression. In addition, blocking NF-κB activation with pyrrolidine dithiocarbamate (PDTC, NF-κB inhibitor) or MSCs-EVs attenuated HI-induced OPN expression in the ipsilateral cortex. This study demonstrates that upregulation of OPN expression in cerebral immune cells aggravated brain damage and inflammation following HI insult. MSCs-EVs suppressed neuroinflammation, synaptic damage and microglial phagocytosis after HI injury by preventing NF-κB-mediated OPN expression in neonate mice.
间充质干细胞（MSCs）衍生的细胞外囊泡（EVs）显著抑制了新生小鼠缺氧缺血（HI）诱导的神经炎症。然而，其潜在机制尚不清楚。骨桥蛋白（OPN）是参与神经炎症的关键分子之一。我们首次在这里证明了 OPN 在 HI 后 EVs 介导的神经炎症中的关键作用。首先，HI 暴露上调了 Iba-1/TMEM119 小胶质细胞和 Iba-1/TMEM119 单核细胞/巨噬细胞中的 OPN 表达。用 LV-shOPN 阻断 OPN mRNA 表达可减轻 HI 暴露后的水肿、梗死体积和炎症细胞因子水平。MSC-EVs 治疗可显著恢复 HI 后突触的重组，并上调突触蛋白的表达，同时降低 OPN 水平。此外，MSC-EVs 治疗可挽救 HI 后存活神经元的小胶质细胞吞噬作用，同时降低 OPN 表达。此外，用吡咯烷二硫代氨基甲酸盐（PDTC，NF-κB 抑制剂）或 MSC-EVs 阻断 NF-κB 激活可减轻 HI 诱导的同侧皮质中 OPN 的表达。这项研究表明，大脑免疫细胞中 OPN 表达的上调加剧了 HI 损伤后的脑损伤和炎症。MSC-EVs 通过防止 NF-κB 介导的 OPN 在新生小鼠中的表达，抑制了 HI 损伤后的神经炎症、突触损伤和小胶质细胞吞噬作用。
