缺血性中风小鼠雌雄大脑中的小胶质细胞异质性

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY
Ángela Del Águila, Ran Zhang, Xinyuan Yu, Lihong Dang, Feng Xu, Jin Zhang, Vaibhav Jain, Jilin Tian, Xiao-Ping Zhong, Huaxin Sheng, Wei Yang
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引用次数: 0

摘要

背景:缺血性中风会引起大脑复杂而持续的免疫反应。长期以来,免疫调节疗法一直有望改善中风的预后,但在临床上却没有一种成功的疗法。之所以没有取得成功,很大程度上是因为我们对免疫细胞如何对中风做出反应的认识不全面。本研究的目的是剖析永久性中风对小胶质细胞(脑实质内的常驻免疫细胞)的影响:方法:采用永久性大脑中动脉闭塞(pMCAO)模型诱导年轻雌雄小鼠发生缺血性中风。方法:采用永久性大脑中动脉闭塞(pMCAO)模型诱导年轻雌雄小鼠脑缺血中风,在pMCAO或假手术后从荧光报告小鼠中分选小胶质细胞,然后进行单细胞RNA测序分析。还采用了流式细胞术、RNA原位杂交、免疫组化、全脑成像和骨髓移植等多种方法来分析小胶质细胞对中风的反应。结果:首先,我们展示了中风后小胶质细胞的形态和空间变化。然后,我们对从假小鼠和中风小鼠体内分离的雌雄小胶质细胞进行了单细胞 RNA 测序分析。数据表明,小胶质细胞对永久性中风的反应没有明显的性别差异。值得注意的是,我们发现了七个潜在的中风相关小胶质细胞集群,包括四个主要集群,其特征分别为疾病相关小胶质细胞样特征、高度增殖状态、巨噬细胞样特征和干扰素(IFN)反应特征。重要的是,我们提供的证据表明,巨噬细胞样群可能代表了人们长期寻找的中风诱导的小胶质细胞亚群,其 CD45 表达增加。最后,鉴于 IFN 反应亚群构成了中风脑部最突出的小胶质细胞群体,我们使用氟达拉滨对 STAT1 信号进行药理学靶向治疗,发现氟达拉滨治疗可改善中风的长期预后:我们的研究结果揭示了中风病理学中小胶质细胞的异质性,并强调了针对特定小胶质细胞群进行有效中风治疗的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Microglial heterogeneity in the ischemic stroke mouse brain of both sexes.

Background: Ischemic stroke elicits a complex and sustained immune response in the brain. Immunomodulatory treatments have long held promise for improving stroke outcomes, yet none have succeeded in the clinical setting. This lack of success is largely due to our incomplete understanding of how immune cells respond to stroke. The objective of the current study was to dissect the effect of permanent stroke on microglia, the resident immune cells within the brain parenchyma.

Methods: A permanent middle cerebral artery occlusion (pMCAO) model was used to induce ischemic stroke in young male and female mice. Microglia were sorted from fluorescence reporter mice after pMCAO or sham surgery and then subjected to single-cell RNA sequencing analysis. Various methods, including flow cytometry, RNA in situ hybridization, immunohistochemistry, whole-brain imaging, and bone marrow transplantation, were also employed to dissect the microglial response to stroke. Stroke outcomes were evaluated by infarct size and behavioral tests.

Results: First, we showed the morphologic and spatial changes in microglia after stroke. We then performed single-cell RNA sequencing analysis on microglia isolated from sham and stroke mice of both sexes. The data indicate no major sexual dimorphism in the microglial response to permanent stroke. Notably, we identified seven potential stroke-associated microglial clusters, including four major clusters characterized by a disease-associated microglia-like signature, a highly proliferative state, a macrophage-like profile, and an interferon (IFN) response signature, respectively. Importantly, we provided evidence that the macrophage-like cluster may represent the long-sought stroke-induced microglia subpopulation with increased CD45 expression. Lastly, given that the IFN-responsive subset constitutes the most prominent microglial population in the stroke brain, we used fludarabine to pharmacologically target STAT1 signaling and found that fludarabine treatment improved long-term stroke outcome.

Conclusions: Our findings shed new light on microglia heterogeneity in stroke pathology and underscore the potential of targeting specific microglial populations for effective stroke therapies.

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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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