Bashore Alexander C, Yan Hanying, Xue Chenyi, Zhu Lucie Y, Kim Eunyoung, Mawson Thomas, Coronel Johana, Chung Allen, Sachs Nadja, Ho Sebastian, Ross Leila S, Kissner Michael, Passegué Emmanuelle, Bauer Robert C, Maegdefessel Lars, Li Mingyao, Reilly Muredach P
Division of Cardiology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY (A.C.B., C.X., L.Y.Z., E.K., T.M., J.C., A.C., S.H., L.S.R., R.C.B., M.P.R.).
Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia (H.Y., M.L.).
Arterioscler Thromb Vasc Biol. 2024 Apr;44(4):930-945. doi: 10.1161/ATVBAHA.123.320524. Epub 2024 Feb 22.
Atherosclerotic 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.
To 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.
We 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.
Our 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.
动脉粥样硬化斑块是由异质性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特征的了解有限。
为了更详细地描述人类颈动脉粥样硬化的特征，我们通过测序和单细胞RNA测序结合转录组和表位的细胞索引，对病变内的所有细胞类型（n = 21；13例有症状）进行分类，以全面多模态地了解动脉粥样硬化的细胞特性及其与临床病理生理学的关联。
我们鉴定出25种细胞群，每种细胞群都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，我们鉴定出2个富含白细胞介素-1β（IL-1B）或C1Q表达的促炎亚群、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上调纤维化途径的SMC特异性基因特征的亚群。进一步的特征分析揭示了SMC和成纤维细胞的各种亚群，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层内膜。利用测序数据的转录组和表位细胞索引，我们开发了一种流式细胞术分析方法，使用细胞表面蛋白CD29、CD142和CD90，从病变中分离SMC衍生的细胞。最后，我们观察到有症状患者与无症状患者相比，吞噬性巨噬细胞、经典激活的内皮细胞以及收缩性和调节性SMC衍生细胞的比例降低，而炎症性SMC在斑块中富集。
我们的动脉粥样硬化细胞群多模态图谱为人类颈动脉粥样硬化独特细胞组成的多样性、表型、位置、分离及临床相关性提供了新的见解。这些发现有助于将心血管疾病易感基因座映射到特定细胞类型，并识别治疗该疾病的新分子和细胞治疗靶点。
