Mocci, Giuseppe and Sukhavasi, Katyayani and Örd, Tiit and Bankier, Sean and Singha, Prosanta and Arasu, Uma Thanigai and Agbabiaje, Olayinka Oluwasegun and Mäkinen, Petri and Ma, Lijiang and Hodonsky, Chani J. and Aherrahrou, Redouane and Muhl, Lars and Liu, Jianping and Gustafsson, Sonja and Byandelger, Byambajav and Wang, Ying and Koplev, Simon and Lendahl, Urban and Owens, Gary K. and Leeper, Nicholas J. and Pasterkamp, Gerard and Vanlandewijck, Michael and Michoel, Tom and Ruusalepp, Arno and Hao, Ke and Ylä-Herttuala, Seppo and Väli, Marika and Järve, Heli and Mokry, Michal and Civelek, Mete and Miller, Clint J. and Kovacic, Jason C. and Kaikkonen, Minna U. and Betsholtz, Christer and Björkegren, Johan L.M. (2024) Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis. Circulation Research, 134 (11). pp.1405-1423. ISSN 0009-7330
Full text not available from this repository.Abstract
BACKGROUND: While our understanding of the single-cell gene expression patterns underlying the transformation of vascular cell types during the progression of atherosclerosis is rapidly improving, the clinical and pathophysiological relevance of these changes remains poorly understood. METHODS: Single-cell RNA sequencing data generated with SmartSeq2 ( approximately 8000 genes/cell) in 16 588 single cells isolated during atherosclerosis progression in Ldlr(-/-)Apob(100/100) mice with human-like plasma lipoproteins and from humans with asymptomatic and symptomatic carotid plaques was clustered into multiple subtypes. For clinical and pathophysiological context, the advanced-stage and symptomatic subtype clusters were integrated with 135 tissue-specific (atherosclerotic aortic wall, mammary artery, liver, skeletal muscle, and visceral and subcutaneous, fat) gene-regulatory networks (GRNs) inferred from 600 coronary artery disease patients in the STARNET (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task) study. RESULTS: Advanced stages of atherosclerosis progression and symptomatic carotid plaques were largely characterized by 3 smooth muscle cells (SMCs), and 3 macrophage subtype clusters with extracellular matrix organization/osteogenic (SMC), and M1-type proinflammatory/Trem2-high lipid-associated (macrophage) phenotypes. Integrative analysis of these 6 clusters with STARNET revealed significant enrichments of 3 arterial wall GRNs: GRN33 (macrophage), GRN39 (SMC), and GRN122 (macrophage) with major contributions to coronary artery disease heritability and strong associations with clinical scores of coronary atherosclerosis severity. The presence and pathophysiological relevance of GRN39 were verified in 5 independent RNAseq data sets obtained from the human coronary and aortic artery, and primary SMCs and by targeting its top-key drivers, FRZB and ALCAM in cultured human coronary artery SMCs. CONCLUSIONS: By identifying and integrating the most gene-rich single-cell subclusters of atherosclerosis to date with a coronary artery disease framework of GRNs, GRN39 was identified and independently validated as being critical for the transformation of contractile SMCs into an osteogenic phenotype promoting advanced, symptomatic atherosclerosis.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 24 Dec 2024 03:03 |
| Last Modified: | 24 Dec 2024 03:03 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/1566 |
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