Integrated Single-Cell Analysis Revealed Novel Subpopulations of Foamy Macrophages in Human Atherosclerotic Plaques

作者：Yunrui Lu, Shuang Wu, Shiyu Zhu, Jian Shen, Chang Liu, Chaoyue Zhao, Sheng’an Su, Hong Ma, Meixiang Xiang, Yao Xie · 发表于：Biomolecules · 年份：2024 · DOI：10.3390/biom14121606 · 被引用次数：9 · 研究领域：Atherosclerosis and Cardiovascular Diseases、Single-cell and spatial transcriptomics、Immune cells in cancer

Foam cell formation is a hallmark of atherosclerosis, yet the cellular complexity within foam cells in human plaques remains unexplored. Here, we integrate published single-cell RNA-sequencing, spatial transcriptomic, and chromatin accessibility sequencing datasets of human atherosclerotic lesions across eight distinct studies. Through this large-scale integration of patient-derived information, we identified foamy macrophages enriched for genes characteristic of the foamy signature. We further re-clustered the foamy macrophages into five unique subsets with distinct potential functions: (i) pro-foamy macrophages, exhibiting relatively high inflammatory and adhesive properties; (ii) phagocytic foamy macrophages, specialized in efferocytosis; (iii) high-efflux foamy macrophages marked by high NR1H3 expression; (iv) mature foamy macrophages prone to programmed cell death; and (v) synthetic subset. Trajectory analysis elucidated a bifurcated differentiation cell fate from pro-foam macrophages toward either the programmed death (iv) or synthetic (v) phenotype. The existence of these foamy macrophage subsets was validated by immunostaining. Moreover, these foamy macrophage subsets exhibited strong potential ligand–receptor interactions. Finally, we conducted Mendelian randomization analyses to identify a possible causal relationship between key regulatory genes along the programmed death pathway in foamy macrophages and atherosclerotic diseases. This study provides a high-resoluti...