Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics
Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques has not been fully assessed. Using single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the pathophysiology underlying human athe...
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| Veröffentlicht in: | Circulation research Jg. 127; H. 11; S. 1437 |
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Sprache: | Englisch |
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United States
06.11.2020
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| ISSN: | 1524-4571, 1524-4571 |
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| Abstract | Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques has not been fully assessed.
Using single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the pathophysiology underlying human atherosclerosis.
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.
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 disease. |
|---|---|
| AbstractList | Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques has not been fully assessed.
Using single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the pathophysiology underlying human atherosclerosis.
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.
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 disease. Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques has not been fully assessed.RATIONALEAtherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques has not been fully assessed.Using single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the pathophysiology underlying human atherosclerosis.OBJECTIVEUsing single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the pathophysiology underlying human atherosclerosis.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.METHODS AND RESULTSWe 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.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 disease.CONCLUSIONSThis 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. |
| Author | Asselbergs, Folkert W Kuiper, Johan de Winther, Menno P J Prange, Koen H M de Jager, Saskia C A Lönnberg, Tapio Slütter, Bram Yla-Herttuala, Seppo Pasterkamp, Gerard Glass, Christopher K den Ruijter, Hester M Kaikkonen, Minna U Slenders, Lotte Depuydt, Marie A C Örd, Tiit Lutgens, Esther Elbersen, Danny de Borst, Gert J Aavik, Einari Boltjes, Arjan Mokry, Michal Bot, Ilze van der Laan, Sander W |
| Author_xml | – sequence: 1 givenname: Marie A C surname: Depuydt fullname: Depuydt, Marie A C organization: Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University, Einsteinweg 55, Leiden, the Netherlands (M.A.C.D., I.B., B.S., J.K.) – sequence: 2 givenname: Koen H M surname: Prange fullname: Prange, Koen H M organization: Amsterdam University Medical Centers-Location AMC, University of Amsterdam, Experimental Vascular Biology, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Meibergdreef 9, the Netherlands (K.H.M.P., M.P.J.d.W.) – sequence: 3 givenname: Lotte surname: Slenders fullname: Slenders, Lotte organization: Laboratory of Clinical Chemistry and Haematology, University Medical Center, Heidelberglaan 100, Utrecht, the Netherlands (L.S., A.B., F.W.A., S.W.v.d.L., M.M., G.P.) – sequence: 4 givenname: Tiit surname: Örd fullname: Örd, Tiit organization: A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.O., E.A., M.U.K., S.Y.-H.) – sequence: 5 givenname: Danny surname: Elbersen fullname: Elbersen, Danny organization: Laboratory for Experimental Cardiology (D.E., S.C.A.d.J), University Medical Center Utrecht, Heidelberglaan 100, the Netherlands – sequence: 6 givenname: Arjan surname: Boltjes fullname: Boltjes, Arjan organization: Laboratory of Clinical Chemistry and Haematology, University Medical Center, Heidelberglaan 100, Utrecht, the Netherlands (L.S., A.B., F.W.A., S.W.v.d.L., M.M., G.P.) – sequence: 7 givenname: Saskia C A surname: de Jager fullname: de Jager, Saskia C A organization: Laboratory for Experimental Cardiology (D.E., S.C.A.d.J), University Medical Center Utrecht, Heidelberglaan 100, the Netherlands – sequence: 8 givenname: Folkert W surname: Asselbergs fullname: Asselbergs, Folkert W organization: Laboratory of Clinical Chemistry and Haematology, University Medical Center, Heidelberglaan 100, Utrecht, the Netherlands (L.S., A.B., F.W.A., S.W.v.d.L., M.M., G.P.) – sequence: 9 givenname: Gert J surname: de Borst fullname: de Borst, Gert J organization: Vascular Surgery (G.J.d.B.), University Medical Center Utrecht, Heidelberglaan 100, the Netherlands – sequence: 10 givenname: Einari surname: Aavik fullname: Aavik, Einari organization: A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.O., E.A., M.U.K., S.Y.-H.) – sequence: 11 givenname: Tapio surname: Lönnberg fullname: Lönnberg, Tapio organization: Turku Bioscience Centre, University of Turku and Åbo Akademi University, Finland (T.L.) – sequence: 12 givenname: Esther surname: Lutgens fullname: Lutgens, Esther organization: German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany (E.L., M.P.J.d.W.) – sequence: 13 givenname: Christopher K surname: Glass fullname: Glass, Christopher K organization: School of Medicine (C.K.G.), University of California San Diego, CA – sequence: 14 givenname: Hester M surname: den Ruijter fullname: den Ruijter, Hester M organization: Cardiology (H.M.d.R., M.M.), University Medical Center Utrecht, Heidelberglaan 100, the Netherlands – sequence: 15 givenname: Minna U surname: Kaikkonen fullname: Kaikkonen, Minna U organization: A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.O., E.A., M.U.K., S.Y.-H.) – sequence: 16 givenname: Ilze surname: Bot fullname: Bot, Ilze organization: Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University, Einsteinweg 55, Leiden, the Netherlands (M.A.C.D., I.B., B.S., J.K.) – sequence: 17 givenname: Bram surname: Slütter fullname: Slütter, Bram organization: Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University, Einsteinweg 55, Leiden, the Netherlands (M.A.C.D., I.B., B.S., J.K.) – sequence: 18 givenname: Sander W surname: van der Laan fullname: van der Laan, Sander W organization: Laboratory of Clinical Chemistry and Haematology, University Medical Center, Heidelberglaan 100, Utrecht, the Netherlands (L.S., A.B., F.W.A., S.W.v.d.L., M.M., G.P.) – sequence: 19 givenname: Seppo surname: Yla-Herttuala fullname: Yla-Herttuala, Seppo organization: A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (T.O., E.A., M.U.K., S.Y.-H.) – sequence: 20 givenname: Michal surname: Mokry fullname: Mokry, Michal organization: Cardiology (H.M.d.R., M.M.), University Medical Center Utrecht, Heidelberglaan 100, the Netherlands – sequence: 21 givenname: Johan surname: Kuiper fullname: Kuiper, Johan organization: Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University, Einsteinweg 55, Leiden, the Netherlands (M.A.C.D., I.B., B.S., J.K.) – sequence: 22 givenname: Menno P J surname: de Winther fullname: de Winther, Menno P J organization: German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany (E.L., M.P.J.d.W.) – sequence: 23 givenname: Gerard surname: Pasterkamp fullname: Pasterkamp, Gerard organization: Laboratory of Clinical Chemistry and Haematology, University Medical Center, Heidelberglaan 100, Utrecht, the Netherlands (L.S., A.B., F.W.A., S.W.v.d.L., M.M., G.P.) |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32981416$$D View this record in MEDLINE/PubMed |
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