Reactive microglia and astrocytes in neonatal intraventricular hemorrhage model are blocked by mesenchymal stem cells
Reactive microglia and astrocytes in neonatal intraventricular hemorrhage model are blocked by mesenchymal stem cells
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DOI：
10.1002/glia.23712
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发表时间：
2019-08-23
期刊：
影响因子：
6.2
通讯作者：
Song, Mi-Ryoung
中科院分区：
文献类型：
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作者：
Kim, Seojeong;Kim, Young Eun;Song, Mi-Ryoung
早产儿严重脑室内出血（IVH）引发反应性神经胶质瘤，引起急性神经元死亡和神经胶质瘢痕形成。在IVH模型中，间充质干细胞（MSCs）移植经常显示出中枢神经系统恢复的改善，但这种反应是否与反应性胶质细胞有关尚不清楚。在此，我们认为MSCs阻碍反应性小胶质细胞的反应，而不是星形胶质细胞，从而阻断神经元损伤。单独的星形胶质细胞在凝血酶处理模拟的出血条件下表现出轻微的反应性，并且这种反应不会被体外msc条件培养基（MSC-CM）阻断。相反，凝血酶诱导的小胶质细胞激活和促炎细胞因子的释放被MSC-CM抑制。有趣的是，星形胶质细胞与小胶质细胞共培养时表现出更大的反应性反应，而这种反应在MSC-CM的存在下被消除。小胶质细胞中的基因表达谱显示，凝血酶治疗改变了免疫反应和促炎细胞因子基因的转录水平。这一结果与STAT1和p38 MAPK的强大磷酸化相吻合，这可能负责促炎细胞因子的产生和释放。此外，应用MSC-CM可降低凝血酶介导的STAT1和p38 MAPK的磷酸化，支持MSCs在出血条件下的急性抗炎作用。与此一致，在stat1缺失的小鼠中，小胶质细胞的激活和随之而来的细胞因子释放受到损害。然而，在stat1缺失的星形胶质细胞中，反应性反应得以维持。综上所述，我们的研究结果表明，MSCs主要阻断小胶质细胞的激活，涉及stat1介导的细胞因子释放和随后反应性星形胶质细胞的减少。
Severe intraventricular hemorrhage (IVH) in premature infants triggers reactive gliosis, causing acute neuronal death and glial scar formation. Transplantation of mesenchymal stem cells (MSCs) has often showed improved CNS recovery in an IVH model, but whether this response is related to reactive glial cells is still unclear. Herein, we suggest that MSCs impede the response of reactive microglia rather than astrocytes, thereby blocking neuronal damage. Astrocytes alone showed mild reactiveness under hemorrhagic conditions mimicked by thrombin treatment, and this was not blocked by MSC-conditioned medium (MSC-CM) in vitro. In contrast, thrombin-induced microglial activation and release of proinflammatory cytokines were inhibited by MSC-CM. Interestingly, astrocytes showed greater reactive response when co-cultured with microglia, and this was abolished in the presence of MSC-CM. Gene expression profiles in microglia revealed that transcript levels of genes for immune response and proinflammatory cytokines were altered by thrombin treatment. This result coincided with the robust phosphorylation of STAT1 and p38 MAPK, which might be responsible for the production and release of proinflammatory cytokines. Furthermore, application of MSC-CM diminished thrombin-mediated phosphorylation of STAT1 and p38 MAPK, supporting the acute anti-inflammatory role of MSCs under hemorrhagic conditions. In line with this, activation of microglia and consequent cytokine release were impaired in Stat1-null mice. However, reactive response in Stat1-deficient astrocytes was maintained. Taken together, our results demonstrate that MSCs mainly block the activation of microglia involving STAT1-mediated cytokine release and subsequent reduction of reactive astrocytes.