6 research outputs found
Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics
RATIONALE: Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of
human plaques has not been fully assessed.
OBJECTIVE: Using single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the
pathophysiology underlying human atherosclerosis.
METHODS AND RESULTS: We performed single-cell RNA and single-cell ATAC sequencing on human carotid atherosclerotic
plaques to define the cells at play and determine their transcriptomic and epigenomic characteristics. We identified 14
distinct cell populations including endothelial cells, smooth muscle cells, mast cells, B cells, myeloid cells, and T cells and
identified multiple cellular activation states and suggested cellular interconversions. Within the endothelial cell population,
we defined subsets with angiogenic capacity plus clear signs of endothelial to mesenchymal transition. CD4+ and CD8+
T cells showed activation-based subclasses, each with a gradual decline from a cytotoxic to a more quiescent phenotype.
Myeloid cells included 2 populations of proinflammatory macrophages showing IL (interleukin) 1B or TNF (tumor necrosis
factor) expression as well as a foam cell-like population expressing TREM2 (triggering receptor expressed on myeloid
cells 2) and displaying a fibrosis-promoting phenotype. ATACseq data identified specific transcription factors associated
with the myeloid subpopulation and T cell cytokine profiles underlying mutual activation between both cell types. Finally,
cardiovascular disease susceptibility genes identified using public genome-wide association studies data were particularly
enriched in lesional macrophages, endothelial, and smooth muscle cells.
CONCLUSIONS: This study provides a transcriptome-based cellular landscape of human atherosclerotic plaques and highlights
cellular plasticity and intercellular communication at the site of disease. This detailed definition of cell communities at play
in atherosclerosis will facilitate cell-based mapping of novel interventional targets with direct functional relevance for the
treatment of human diseas