Unravelling atherosclerotic heterogeneity by single cell RNA sequencing.
Unravelling atherosclerotic heterogeneity by single cell RNA sequencing.
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DOI：
10.1097/mol.0000000000000559
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发表时间：
2018-12
影响因子：
4.4
通讯作者：
I. McCracken;Richard S. Taylor;N. Henderson;J. Sluimer;A. Baker
中科院分区：
文献类型：
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作者：
I. McCracken;Richard S. Taylor;N. Henderson;J. Sluimer;A. Baker
DOI:10.1097/MOL.0000000000000559 动脉粥样硬化斑块是一个包含免疫细胞和基质细胞的复杂环境，许多细胞会转变表型，甚至转变为其他细胞类型 [1–4]。之前描述动脉粥样硬化异质性的尝试受到了对预定义细胞表面标记的要求的限制，从而否定了新的群体发现[5&]。因此，细胞异质性的表征很差并且可能过于简单化[6-8]。动脉粥样硬化领域的这一挑战最近已通过单细胞 RNA 测序 (scRNA-seq) 的应用得到解决，允许以单细胞分辨率进行转录组分析 [9 && ,10 && ]。与之前依赖先验的方法相比，scRNA-seq 可以对异质群体中的细胞身份进行公正、全面的表征 [5 & ]。重要的是，基于液滴的微流体平台允许对数千个细胞进行并行测序[11]。最近的两项研究利用基于液滴的 scRNA-seq 平台分别绘制了对照小鼠和脂肪喂养的低密度脂蛋白受体缺陷 (Ldlr / ) [9 && ] 或载脂蛋白 E (Apoe / ) 小鼠 [10 && ] 的白细胞异质性。无监督聚类显示每个模型中有超过 10 个聚类，并且随着疾病的进展，异质性增加。这两篇出版物均表明动脉粥样硬化斑块主要由巨噬细胞和 T 细胞组成。与 Ldlr/ 小鼠中观察到的相比，Apoe/ 小鼠中巨噬细胞占主动脉白细胞的比例较低，尽管两种模型中巨噬细胞的比例随着疾病进展而增加 [9 && ,10 && ]。重要的是，scRNA-seq 鉴定了一个新的巨噬细胞簇（通过 TREM2 的富集表达来鉴定），并改变了对巨噬细胞生物学的普遍看法，因为鉴定的炎症和常驻巨噬细胞群体与极化的 M1 和 M2 巨噬细胞表型仅表现出微弱的相似性，再次凸显了当前分类系统的局限性 [10 && ]。
DOI:10.1097/MOL.0000000000000559 The atherosclerotic plaque is a complex environment containing immune and stromal cells, many switching phenotype or even transitioning to alternative cell types [1–4]. Previous attempts to characterize heterogeneity in atherosclerosis have been limited by the requirement for predefined cell surface markers, thus negating new population discovery [5 & ]. Consequently, cellular heterogeneity is poorly characterized and likely oversimplified [6–8]. This challenge in the atherosclerosis field has recently been addressed by the utility of single cell RNA sequencing (scRNA-seq), allowing transcriptome analysis at a single cell resolution [9 && ,10 && ]. In contrast to previous priori-dependant approaches, scRNA-seq allows for the unbiased, comprehensive characterization of cellular identity within a heterogeneous population [5 & ]. Importantly, droplet-based microfluidic platforms permit the sequencing of thousands of cells in parallel [11]. Two recent studies have utilized a droplet-based scRNA-seq platform to map leukocyte heterogeneity in control and fat-fed low-density lipoprotein receptor deficient (Ldlr / ) [9 && ] or apolipoprotein E (Apoe / ) mice [10 && ], respectively. Unsupervised clustering revealed more than 10 clusters in each model, with increased heterogeneity with advancing disease. Both publications show that the atherosclerotic plaques were predominantly composed of macrophages and T cells. Macrophages were found to account for a lower proportion of aortic leukocytes in Apoe / mice compared to that observed in Ldlr / mice, although the proportion of macrophages increased with disease progression in both models [9 && ,10 && ]. Importantly, scRNA-seq identified a new macrophage cluster (identified by enriched expression of TREM2) and changed pervading views on macrophage biology, as the identified inflammatory and resident macrophage populations demonstrated only a weak resemblance to polarized M1 and M2 macrophage phenotypes, again highlighting the limitations of the current classification system [10 && ].