Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Winkels, H; Ehinger, E; Vassallo, M; Buscher, K; Dinh, HQ; Kobiyama, K; Hamers, AAJ; Cochain, C; Vafadarnejad, E; Saliba, AE; Zernecke, A; Pramod, AB; Ghosh, AK; Anto Michel, N; Hoppe, N; Hilgendorf, I; Zirlik, A; Hedrick, CC; Ley, K; Wolf, D.
Atlas of the Immune Cell Repertoire in Mouse Atherosclerosis Defined by Single-Cell RNA-Sequencing and Mass Cytometry.
Circ Res. 2018; 122(12):1675-1688
Doi: 10.1161/CIRCRESAHA.117.312513
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- Co-Autor*innen der Med Uni Graz
- Anto Michel Nathaly
- Zirlik Andreas
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- Abstract:
- Atherosclerosis is a chronic inflammatory disease that is driven by the interplay of pro- and anti-inflammatory leukocytes in the aorta. Yet, the phenotypic and transcriptional diversity of aortic leukocytes is poorly understood. We characterized leukocytes from healthy and atherosclerotic mouse aortas in-depth by single-cell RNA-sequencing and mass cytometry (cytometry by time of flight) to define an atlas of the immune cell landscape in atherosclerosis. Using single-cell RNA-sequencing of aortic leukocytes from chow diet- and Western diet-fed Apoe-/- and Ldlr-/- mice, we detected 11 principal leukocyte clusters with distinct phenotypic and spatial characteristics while the cellular repertoire in healthy aortas was less diverse. Gene set enrichment analysis on the single-cell level established that multiple pathways, such as for lipid metabolism, proliferation, and cytokine secretion, were confined to particular leukocyte clusters. Leukocyte populations were differentially regulated in atherosclerotic Apoe-/- and Ldlr-/- mice. We confirmed the phenotypic diversity of these clusters with a novel mass cytometry 35-marker panel with metal-labeled antibodies and conventional flow cytometry. Cell populations retrieved by these protein-based approaches were highly correlated to transcriptionally defined clusters. In an integrated screening strategy of single-cell RNA-sequencing, mass cytometry, and fluorescence-activated cell sorting, we detected 3 principal B-cell subsets with alterations in surface markers, functional pathways, and in vitro cytokine secretion. Leukocyte cluster gene signatures revealed leukocyte frequencies in 126 human plaques by a genetic deconvolution strategy. This approach revealed that human carotid plaques and microdissected mouse plaques were mostly populated by macrophages, T-cells, and monocytes. In addition, the frequency of genetically defined leukocyte populations in carotid plaques predicted cardiovascular events in patients. The definition of leukocyte diversity by high-dimensional analyses enables a fine-grained analysis of aortic leukocyte subsets, reveals new immunologic mechanisms and cell-type-specific pathways, and establishes a functional relevance for lesional leukocytes in human atherosclerosis. © 2018 American Heart Association, Inc.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Aortic Diseases - pathology
- Apolipoproteins E - deficiency
- Apolipoproteins E - genetics
- Atherosclerosis - pathology
- B-Lymphocytes - pathology
- Flow Cytometry - methods
- Humans -
- Leukocytes - metabolism
- Leukocytes - pathology
- Macrophages - pathology
- Medical Illustration -
- Mice -
- Monocytes - pathology
- Phenotype -
- Receptors, LDL - deficiency
- Receptors, LDL - genetics
- Sequence Analysis, RNA - methods
- Single-Cell Analysis - methods
- T-Lymphocytes - pathology
- Transcriptome -
- Find related publications in this database (Keywords)
- atherosclerosis
- flow cytometry
- immune system
- leukocytes
- lymphocytes
- macrophages
- mass cytometry
- single-cell RNA-sequencing