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Distinguishing features of microglia- and monocyte-derived macrophages after stroke
Acta Neuropathologica ( IF 12.7 ) Pub Date : 2017-12-16 , DOI: 10.1007/s00401-017-1795-6
Golo Kronenberg , Ria Uhlemann , Nadine Richter , Friederike Klempin , Stephanie Wegner , Lilian Staerck , Susanne Wolf , Wolfgang Uckert , Helmut Kettenmann , Matthias Endres , Karen Gertz

After stroke, macrophages in the ischemic brain may be derived from either resident microglia or infiltrating monocytes. Using bone marrow (BM)-chimerism and dual-reporter transgenic fate mapping, we here set out to delimit the responses of either cell type to mild brain ischemia in a mouse model of 30 min transient middle cerebral artery occlusion (MCAo). A discriminatory analysis of gene expression at 7 days post-event yielded 472 transcripts predominantly or exclusively expressed in blood-derived macrophages as well as 970 transcripts for microglia. The differentially regulated genes were further collated with oligodendrocyte, astrocyte, and neuron transcriptomes, resulting in a dataset of microglia- and monocyte-specific genes in the ischemic brain. Functional categories significantly enriched in monocytes included migration, proliferation, and calcium signaling, indicative of strong activation. Whole-cell patch-clamp analysis further confirmed this highly activated state by demonstrating delayed outward K+ currents selectively in invading cells. Although both cell types displayed a mixture of known phenotypes pointing to the significance of ‘intermediate states’ in vivo, blood-derived macrophages were generally more skewed toward an M2 neuroprotective phenotype. Finally, we found that decreased engraftment of blood-borne cells in the ischemic brain of chimeras reconstituted with BM from Selplg−/− mice resulted in increased lesions at 7 days and worse post-stroke sensorimotor performance. In aggregate, our study establishes crucial differences in activation state between resident microglia and invading macrophages after stroke and identifies unique genomic signatures for either cell type.



中文翻译:

脑卒中后小胶质细胞和单核细胞衍生巨噬细胞的区别特征

中风后,缺血性脑中的巨噬细胞可能来自驻留的小胶质细胞或浸润的单核细胞。使用骨髓(BM)嵌合和双报告转基因命运映射,我们在这里开始划定30分钟短暂脑中动脉闭塞(MCAo)小鼠模型中任一细胞类型对轻度脑缺血的反应。事件后7天的基因表达差异分析产生了472个转录本,这些转录本主要或专门在血源性巨噬细胞中表达,还有970个小胶质细胞的转录本。进一步将差异调节的基因与少突胶质细胞,星形胶质细胞和神经元转录组进行核对,从而形成了缺血性脑中小胶质细胞和单核细胞特异性基因的数据集。单核细胞中显着丰富的功能类别包括迁移,增殖,和钙信号,表明强烈激活。全细胞膜片钳分析通过证实延迟的向外K进一步证实了这种高度活化的状态+电流选择性地侵入细胞。尽管两种细胞类型均显示出已知表型的混合物,表明体内“中间状态”的重要性,但血源性巨噬细胞通常更倾向于M2神经保护表型。最后,我们发现用Selplg -/-小鼠的BM重构的嵌合体缺血性脑中血源性细胞的植入减少导致第7天损伤增加,并且中风后感觉运动性能下降。总的来说,我们的研究建立了中风后常驻小胶质细胞和侵袭性巨噬细胞之间激活状态的关键差异,并确定了两种细胞类型的独特基因组特征。

更新日期:2017-12-16
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