Institute of Parasitology and Biomedicine López-Neyra, Dept. Cell Biology and Immunology, IPBLN-CSIC, Avda. Conocimiento, PT Ciencias de La Salud, Granada, Spain.
Glia. 2014 Dec;62(12):1932-42. doi: 10.1002/glia.22714. Epub 2014 Jul 3.
Activated microglia play a central role in the course of neurodegenerative diseases as they secrete cytotoxic substances which lead to neuronal cell death. Understanding the mechanisms that drive activation of microglia is essential to reverse this phenotype and to protect from neurodegeneration. With some exceptions, evidence indicates that changes in cell morphology from a star shape to a round and flat shape accompany the process of activation in microglia. In this study, we investigated the effect of adipose-tissue-derived mesenchymal stem cells (ASCs), which exert important anti-inflammatory actions, in microglia morphology. Microglia exposed to ASCs or their secreted factors (conditioned medium) underwent a cell shape change into a ramifying morphology in basal and inflammatory conditions, similar to that observed in microglia found in healthy brain. Colony-stimulating factor-1 secreted by ASCs played a critical role in the induction of this phenotype. Importantly, ASCs reversed the activated round phenotype induced in microglia by bacterial endotoxins. The ramifying morphology of microglia induced by ASCs was associated with a decrease of the proinflammatory cytokines tumor necrosis factor-α and interleukin-6, an increase in phagocytic activity, and the upregulation of neurotrophic factors and of Arginase-1, a marker for M2-like regulatory microglia. In addition, activation of the phosphoinositide-3-kinase/Akt pathway and the RhoGTPases Rac1 and Cdc42 played a major role in the acquisition of this phenotype. Therefore, these RhoGTPases emerge as key players in the ramification of microglia by anti-inflammatory agents like ASCs, being fundamental to maintain the tissue-surveying, central nervous system supporting state of microglia in healthy conditions.
活化的小胶质细胞在神经退行性疾病的发生过程中起核心作用，因为它们分泌细胞毒性物质，导致神经元细胞死亡。了解驱动小胶质细胞活化的机制对于逆转这种表型和防止神经退行性变至关重要。除了一些例外，有证据表明，小胶质细胞从星状形状到圆形和扁平形状的细胞形态变化伴随着其活化过程。在这项研究中，我们研究了脂肪组织来源的间充质干细胞（ASCs）对小胶质细胞形态的影响，ASCs 发挥重要的抗炎作用。暴露于 ASCs 或其分泌因子（条件培养基）的小胶质细胞在基础和炎症条件下发生细胞形态变化，呈分支状形态，类似于在健康大脑中发现的小胶质细胞。ASCs 分泌的集落刺激因子-1在诱导这种表型中起着关键作用。重要的是，ASCs 逆转了细菌内毒素诱导的小胶质细胞活化的圆形表型。ASCs 诱导的小胶质细胞的分支形态与促炎细胞因子肿瘤坏死因子-α和白细胞介素-6的减少、吞噬活性的增加以及神经营养因子和 Arg1 的上调有关，Arg1 是 M2 样调节小胶质细胞的标志物。此外，磷酸肌醇-3-激酶/Akt 通路和 RhoGTPases Rac1 和 Cdc42 的激活在获得这种表型中起着重要作用。因此，这些 RhoGTPases 作为抗炎剂如 ASCs 分支小胶质细胞的关键参与者出现，对于维持小胶质细胞在健康状态下的组织探测、中枢神经系统支持状态至关重要。
