Microanatomy of the human atherosclerotic plaque by single-cell transcriptomics

Depuydt, M.A.C.; Prange, K.H.M.; Slenders, L.; Örd, T.; Elbersen, D.; Boltjes, A.; Jager, S.C.A. de; Asselbergs, F.W.; Borst, G.J. de; Aavik, E.; Lönnberg, T.; Lutgens, E.; Glass, C.K.; Ruijter, H.M. den; Kaikkonen, M.U.; Bot, I.; Slütter, B.; Laan, S.W. van der; Yla-Herttuala, S.; Mokry, M.; Kuiper, J.; Winther, M.P.J. de; Pasterkamp, G.

doi:doi:10.1161/CIRCRESAHA.120.316770

Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques has not been fully assessed.\nUsing single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the pathophysiology underlying human atherosclerosis.\n 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...Show moreAtherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques has not been fully assessed.\nUsing single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the pathophysiology underlying human atherosclerosis.\n 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.\nThis 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 disease.Show less

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Microanatomy of the human atherosclerotic plaque by single-cell transcriptomics