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For decades, the pathological definition of the vulnerable plaque led to invaluable insights into the mechanisms that underlie myocardial infarction and stroke. Beyond plaque rupture, other mechanisms, such as erosion, may elicit thrombotic events underlining the complexity and diversity of the atherosclerotic disease. Novel insights, based on single-cell transcriptomics and other "omics" methods, provide tremendous opportunities in the ongoing search for cell-specific determinants that will fine-tune the description of the thrombosis prone lesion. It coincides with an increasing awareness that knowledge on lesion characteristics, cell plasticity and clinical presentation of ischemic cardiovascular events have shifted over the past decades. This shift correlates with an observed changes of cell composition towards phenotypical stabilizing of human plaques. These stabilization features and mechanisms are directly mediated by the cells present in plaques and can be mimicked in vitro via primary plaque cells derived from human atherosclerotic tissues. In addition, the rapidly evolving of sequencing technologies identify many candidate genes and molecular mechanisms that may influence the risk of developing an atherosclerotic thrombotic event - which bring the next challenge in sharp focus: how to translate these cell-specific insights into tangible functional and translational discoveries?

Atherosclerotic lesions are known for their complex and diverse cellular heterogeneity, yet the exact cellular composition of human plaques remains unclear. Here we aim to provide a comprehensive overview of the cellular content of advanced atherosclerotic lesions using single-cell RNA sequencing (scRNAseq), to increase our understanding of the pathophysiologic processes underlying atherosclerosis.Advanced carotid plaques were obtained from 3 male endarterectomy patients. Plaques were enzymatically digested and live cells were sorted using FACS. Subsequently, we performed scRNAseq on a total of 3456 plaque derived cells.Unsupervised clustering revealed 11 distinct cell populations, including macrophages, CD4+and CD8+T-cells, B-cells, mast cells, endothelial cells, and smooth muscle cells. Interestingly, we were able to distinguish multiple subclusters for the smooth muscle cells, macrophages, and T-cells. We observed a contractile and synthetic smooth muscle cell cluster and three different macrophage clusters, including inflammatory, wound healing and antigen presenting macrophages. Finally, CD8+T-cells could be subdivided into three clusters based on their activation state, with a clear division between cytolytic effectors and quiescent memory CD8+T-cells. We developed a technique to perform scRNAseq on advanced human atherosclerotic lesions to unravel the cellular landscape within the plaques. We now provide, for the first time, an explicit expression profile of the different cells and their subtypes in atherosclerosis.