Year: 2024
Type: article
Study design: Observational Study
Abstract: BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: National Institutes of Health, Irving Medical Center, Columbia University, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Awards: G144283012, Computational and functional strategies to decipher lncRNAs in human atherosclerosis, Elucidation of Tissue-Specific Transcriptomic Profiles in Cardio-metabolic Disease, Regulation of lipoprotein metabolism by adipose-specific Tribbles-1, G5783583872, Integrative analysis of bulk and single-cell RNA-seq data for cardiometabolic disease, Statistical Methods for Single-Cell Transcriptomics, G9000090167, Clinical and Translational Science Award, Smooth muscle cell-derived cell fates and cellular interactions in atherosclerotic plaque stability in disease progression and regression., Molecular Mechanisms of TRIB1 Regulation of Hepatic Metabolism, Identification of smooth muscle cell genes causal in atherosclerotic plaque stability and cardiovascular disease risk, Postdoctoral Training in Arteriosclerosis Research, Cancer Center Support Grant
OpenAlex ID: W4392080105