Single-cell RNA-seq analysis of human coronary arteries using an enhanced workflow reveals SMC transitions and candidate drug targets

Feng, Wei; Hodonsky, Chani J.; Turner, Adam; Wong, Doris; Song, Yipei; Barrientos, Nelson B.; Miller, Clint L.

doi:10.1101/2020.10.27.357715

Cited by 10 publications

(9 citation statements)

References 48 publications

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“…To confirm these findings, they incorporated large GWAS datasets and found that individuals with decreased TCF21 expression resulting from genetic variants (SNPs) were at increased risk of CVD events. Recently, this trans-differentiation of VSMCs was further confirmed in human coronary arteries by Ma et al [90], who applied pseudotemporal ordering to an existing scRNA dataset to reveal distinct VSMC-derived chondroblast-like and fibroblast-like lineages. Importantly, the clinical implications of this phenomenon are underscored by a recent study by Pan et al [91] which demonstrated that blocking the differentiation of VSMCs to an intermediate phenotype (SEM) reduces atherosclerotic burden and enhances lesion stability.…”

Section: Translating Single-cell Approaches To Human Diseasementioning

confidence: 79%

Single cell analyses to understand the immune continuum in atherosclerosis

2021

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Atherosclerosis is initiated by the accumulation of lipids in the arterial wall that trigger a complex and poorly understood network of inflammatory processes. At the same time, recent clinical findings reveal that targeting specific immune alterations in patients with cardiovascular disease (CVD) represents a promising approach to preventing recurrent cardiovascular events. In order to achieve these tailored therapies, it is critical to resolve the heterogenous environment of the atherosclerotic lesion and decipher the complex structural and functional changes which immune cells undergo throughout disease progression. Recently, single-cell approaches including single cell mass cytometry by time of flight (CyTOF), single cell RNA sequencing (scRNA-seq) and Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) have emerged as valuable tools in resolving cellular plasticity within atherosclerotic lesions. In this review, we will discuss the most important insights that have been gleaned from the application of these single-cell approaches to validated experimental models of atherosclerosis. Additionally, as clinical progress in treatment of the disease depends on the translation of discoveries to human tissues, we will also examine the challenges associated with the application of single-cell approaches to human vascular tissue and the discoveries made by the initial efforts in this direction. Finally, we will analyze the advantages and limitations of dissociative single-cell approaches and how novel in-situ technologies could advance the field by allowing for the investigation of individual cells while preserving the heterogenous architecture of the atherosclerotic lesion.

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Section: Translating Single-cell Approaches To Human Diseasementioning

confidence: 79%

Single cell analyses to understand the immune continuum in atherosclerosis

2021

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“…Similar to these observations in mice, the single-cell RNA sequencing dataset by Wirka et al from human atherosclerotic coronary arteries showed that PDGFB was mainly expressed in macrophages and endothelial cells, albeit by a low percentage of cells. PDGFA was mainly expressed by mesenchymal cells in the human plaque ( Figure S1 in Supplementary Material [ 25 , 26 ]).…”

Section: Resultsmentioning

confidence: 99%

A Switch from Cell-Associated to Soluble PDGF-B Protects against Atherosclerosis, despite Driving Extramedullary Hematopoiesis

Tillie

Theelen

Kuijk

et al. 2021

Cells

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Platelet-derived growth factor B (PDGF-B) is a mitogenic, migratory and survival factor. Cell-associated PDGF-B recruits stabilizing pericytes towards blood vessels through retention in extracellular matrix. We hypothesized that the genetic ablation of cell-associated PDGF-B by retention motif deletion would reduce the local availability of PDGF-B, resulting in microvascular pericyte loss, microvascular permeability and exacerbated atherosclerosis. Therefore, Ldlr-/-Pdgfbret/ret mice were fed a high cholesterol diet. Although plaque size was increased in the aortic root of Pdgfbret/ret mice, microvessel density and intraplaque hemorrhage were unexpectedly unaffected. Plaque macrophage content was reduced, which is likely attributable to increased apoptosis, as judged by increased TUNEL+ cells in Pdgfbret/ret plaques (2.1-fold) and increased Pdgfbret/ret macrophage apoptosis upon 7-ketocholesterol or oxidized LDL incubation in vitro. Moreover, Pdgfbret/ret plaque collagen content increased independent of mesenchymal cell density. The decreased macrophage matrix metalloproteinase activity could partly explain Pdgfbret/ret collagen content. In addition to the beneficial vascular effects, we observed reduced body weight gain related to smaller fat deposition in Pdgfbret/ret liver and adipose tissue. While dampening plaque inflammation, Pdgfbret/ret paradoxically induced systemic leukocytosis. The increased incorporation of 5-ethynyl-2′-deoxyuridine indicated increased extramedullary hematopoiesis and the increased proliferation of circulating leukocytes. We concluded that Pdgfbret/ret confers vascular and metabolic effects, which appeared to be protective against diet-induced cardiovascular burden. These effects were unrelated to arterial mesenchymal cell content or adventitial microvessel density and leakage. In contrast, the deletion drives splenic hematopoiesis and subsequent leukocytosis in hypercholesterolemia.

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“…Studies on the immune-cell subsets and cellular composition of aortic atherosclerotic lesions in mouse models and human carotid and coronary arteries by cytometry or cellsorting methods (flow cytometry, CyTOF, and scRNA-seq) have yielded discrepant results due to differences in study design, methodological approaches, and biomaterial sources 11,16,17,[23][24][25][26][27][28]35,[44][45][46] (Fig. 3a and b).…”

Section: Discussionmentioning

confidence: 99%

“…The proportions of T, B, and myeloid cells were nearly equal in coronary arteries (approximately 10% for each cell type). 46 Media and adventitia of atherosclerotic plaques contain most of VSMCs and B cells; therefore, in a carotid lesion that lacks these tissues, counts of some leukocytes are overestimated in comparison with a whole artery. Winkels et al (2018) found predominant accumulation of myeloid cells and T cells in microdissected mouse aortic plaques and human carotid plaques while B cells predominated in the adventitia and proved to be only a minor subpopulation in plaques.…”

Section: Discussionmentioning

confidence: 99%

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Cellular composition of human early and advanced coronary atherosclerotic lesions

Sharysh

Марков

Grigoryeva

et al. 2021

Preprint

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Objective: Here, we identify and quantify leukocytes, macrophages, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs) with contractile and macrophage-like phenotypes by flow cytometry to compare human early and advanced coronary atherosclerotic plaques. Approach and Results: Sixteen coronary atherosclerotic lesions of 6 patients (3 women, 3 men, age 82 ± 9 years), including one case of restenosis after coronary stenting, were collected at autopsy. The cause of death of all patients was acute myocardial infarction. The lesions were categorized into early (EALs, n = 5) and advanced (AALs, n = 11) atherosclerotic stages. We analyzed a cell suspension stained with antibodies against CD45, CD68, CD31, and aSMA (ACTA2). We noted a decrease in the number of CD45+ cells and an increase in the CD45+CD68+ subpopulation of leukocytes from EALs to AALs. Numbers of CD45-aSMA+CD68+ cells positively correlated with the CD45+CD68+ macrophage number (r = 0.81; rho = 0.64; p < 0.05) and the histological type of an atherosclerotic lesion (r = 0.81; rho = 0.87; p < 0.05). As an interesting case, we analyzed the cellular composition of the stented coronary artery and revealed significantly greater numbers of macrophages, aSMA+CD68+ VSMCs, and ECs in comparison with nonstented plaques. Conclusions: Human early and advanced coronary atherosclerotic lesions differ in their counts of leukocytes and leukocyte subpopulations. For the first time, aSMA+CD68+ VSMCs were identified in early atherosclerotic stages of coronary arteries. Additionally, the restenotic coronary lesion contains mostly cells and is enriched in ECs, macrophages, and aSMA+CD68+ VSMCs in particular.

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Single-cell RNA-seq analysis of human coronary arteries using an enhanced workflow reveals SMC transitions and candidate drug targets

Cited by 10 publications

References 48 publications

Single cell analyses to understand the immune continuum in atherosclerosis

Single cell analyses to understand the immune continuum in atherosclerosis

A Switch from Cell-Associated to Soluble PDGF-B Protects against Atherosclerosis, despite Driving Extramedullary Hematopoiesis

Cellular composition of human early and advanced coronary atherosclerotic lesions

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