A core transcriptional signature of human microglia: Derivation and utility in describing region-dependent alterations associated with Alzheimer's disease
A core transcriptional signature of human microglia: Derivation and utility in describing region-dependent alterations associated with Alzheimer's disease
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DOI：
10.1002/glia.23572
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发表时间：
2019-07-01
期刊：
影响因子：
6.2
通讯作者：
Freeman, Tom C.
中科院分区：
文献类型：
--
作者：
Patir, Anirudh;Shih, Barbara;Freeman, Tom C.
小胶质细胞在神经退行性疾病和神经炎症性疾病中的关键作用日益受到重视，这突出了表征其在健康和疾病中的功能的必要性。在小鼠中的研究已经应用了小胶质细胞的全转录组分析，以揭示小胶质细胞个体发育、功能概况和表型多样性的关键特征。虽然相似，但人类小胶质细胞与其小鼠对应物表现出明显的差异，强调需要更好地了解人类小胶质细胞概况。在检查已发表的小胶质细胞基因签名时，观察到研究之间的一致性有限。因此，我们试图通过对现有转录组数据集的全面分析来获得人类中枢神经系统（CNS）的核心小胶质细胞特征。从众多供体的CNS的各个区域分离的源自细胞和组织的九个数据集独立地进行无偏相关网络分析。从每个数据集中，确定了对应于小胶质细胞的共表达基因的列表，其中249个基因在它们之间高度保守。该核心特征包括已知的小胶质细胞标志物，并且与其他特征相比，提供了在CNS背景下对小胶质细胞特异性的基因集。该签名的效用通过其在检测老化和阿尔茨海默病中的定性和定量区域特异性改变中的使用而得到证明。这些分析强调了小胶质细胞在脆弱的大脑区域（如内嗅皮层和海马）中的反应性反应，另外还涉及与疾病进展相关的途径。我们相信这一资源和这里描述的分析，将支持进一步研究人类小胶质细胞在中枢神经系统健康和疾病中的贡献。
Growing recognition of the pivotal role microglia play in neurodegenerative and neuroinflammatory disorders has accentuated the need to characterize their function in health and disease. Studies in mouse have applied transcriptome-wide profiling of microglia to reveal key features of microglial ontogeny, functional profile, and phenotypic diversity. While similar, human microglia exhibit clear differences to their mouse counterparts, underlining the need to develop a better understanding of the human microglial profile. On examining published microglia gene signatures, limited consistency was observed between studies. Hence, we sought to derive a core microglia signature of the human central nervous system (CNS), through a comprehensive analysis of existing transcriptomic datasets. Nine datasets derived from cells and tissues, isolated from various regions of the CNS across numerous donors, were subjected independently to an unbiased correlation network analysis. From each dataset, a list of coexpressing genes corresponding to microglia was identified, with 249 genes highly conserved between them. This core signature included known microglial markers, and compared with other signatures provides a gene set specific to microglia in the context of the CNS. The utility of this signature was demonstrated by its use in detecting qualitative and quantitative region-specific alterations in aging and Alzheimer's disease. These analyses highlighted the reactive response of microglia in vulnerable brain regions such as the entorhinal cortex and hippocampus, additionally implicating pathways associated with disease progression. We believe this resource and the analyses described here, will support further investigations to the contribution of human microglia in CNS health and disease.