High-Dimensional Single-Cell Multimodal Landscape of Human Carotid Atherosclerosis.
High-Dimensional Single-Cell Multimodal Landscape of Human Carotid Atherosclerosis.
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人颈动脉粥样硬化的高维单细胞多模态景观。
DOI：
10.1101/2023.07.13.23292633
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Reilly,Mu
中科院分区：
文献类型：
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作者：
Bashore,AlexanderC;Yan,Hanying;Xue,Chenyi;Zhu,LucieY;Kim,Eunyoung;Mawson,Thomas;Coronel,Johana;Chung,Allen;Ho,Sebastian;Ross,LeilaS;Kissner,Michael;Passegué,Emmanuelle;Bauer,RobertC;Maegdefessel,Lars;Li,Mingyao;Reilly,Mu
背景动脉粥样硬化斑块是由异质细胞混合物组成的复杂组织。然而，我们对这些病变内细胞的全面转录和表型景观的了解是有限的。方法为了更详细地描述人类颈动脉粥样硬化的景观，我们结合了通过测序和单细胞RNA测序对转录组和表位进行细胞索引，对病变内的所有细胞类型（n = 21；13有症状）进行分类，以实现对动脉粥样硬化的细胞身份及其与临床关系的全面多模式理解结果我们鉴定了 25 个细胞群，每个细胞群都具有独特的多组学特征，包括巨噬细胞、T 细胞、NK（自然杀伤）细胞、肥大细胞、B 细胞、浆细胞、中性粒细胞、树突状细胞、内皮细胞、成纤维细胞和平滑肌细胞 (SMC)。在巨噬细胞中，我们鉴定了 2 个富含 IL-1B（白介素-1B）或 C1Q 表达的促炎症亚群、2 个 TREM2 阳性泡沫细胞（1 个表达炎症基因）以及具有增殖基因特征和 SMC 特异性基因特征且纤维化途径上调的亚群。进一步的表征揭示了 SMC 和成纤维细胞的各种子集，包括 SMC 衍生的泡沫细胞。这些泡沫状 SMC 位于冠状动脉粥样硬化病变的深部内膜中。通过测序数据利用转录组和表位的细胞索引，我们开发了一个流式细胞术面板，使用细胞表面蛋白 CD29、CD142 和 CD90，从病变中分离 SMC 衍生细胞。最后，我们观察到胞吞型巨噬细胞、经典激活的内皮细胞以及收缩和调节的 SMC 衍生细胞的比例减少，而炎症 SMC 在有临床症状的患者与无症状患者的斑块中富集。结论我们的动脉粥样硬化细胞群多模式图谱为人类颈动脉独特细胞组成的多样性、表型、位置、分离和临床相关性提供了新的见解。动脉粥样硬化。这些发现有助于绘制心血管疾病易感位点与特定细胞类型的图谱，以及识别用于治疗该疾病的新型分子和细胞治疗靶点。
BACKGROUNDAtherosclerotic plaques are complex tissues composed of a heterogeneous mixture of cells. However, our understanding of the comprehensive transcriptional and phenotypic landscape of the cells within these lesions is limited.METHODSTo characterize the landscape of human carotid atherosclerosis in greater detail, we combined cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing to classify all cell types within lesions (n=21; 13 symptomatic) to achieve a comprehensive multimodal understanding of the cellular identities of atherosclerosis and their association with clinical pathophysiology.RESULTSWe identified 25 cell populations, each with a unique multiomic signature, including macrophages, T cells, NK (natural killer) cells, mast cells, B cells, plasma cells, neutrophils, dendritic cells, endothelial cells, fibroblasts, and smooth muscle cells (SMCs). Among the macrophages, we identified 2 proinflammatory subsets enriched in IL-1B (interleukin-1B) or C1Q expression, 2 TREM2-positive foam cells (1 expressing inflammatory genes), and subpopulations with a proliferative gene signature and SMC-specific gene signature with fibrotic pathways upregulated. Further characterization revealed various subsets of SMCs and fibroblasts, including SMC-derived foam cells. These foamy SMCs were localized in the deep intima of coronary atherosclerotic lesions. Utilizing cellular indexing of transcriptomes and epitopes by sequencing data, we developed a flow cytometry panel, using cell surface proteins CD29, CD142, and CD90, to isolate SMC-derived cells from lesions. Lastly, we observed reduced proportions of efferocytotic macrophages, classically activated endothelial cells, and contractile and modulated SMC-derived cells, while inflammatory SMCs were enriched in plaques of clinically symptomatic versus asymptomatic patients.CONCLUSIONSOur multimodal atlas of cell populations within atherosclerosis provides novel insights into the diversity, phenotype, location, isolation, and clinical relevance of the unique cellular composition of human carotid atherosclerosis. These findings facilitate both the mapping of cardiovascular disease susceptibility loci to specific cell types and the identification of novel molecular and cellular therapeutic targets for the treatment of the disease.