Emerging Concepts of Vascular Cell Clonal Expansion in Atherosclerosis

Misra, Ashish; Rehan, Rajan; Lin, Alexander; Patel, Sanjay; Fisher, Edward A.

doi:10.1161/atvbaha.121.316093

Cited by 15 publications

(13 citation statements)

References 109 publications

(179 reference statements)

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“…VSMCs from the tunica media are known to extensively proliferate and migrate to the tunica intima forming intimal hyperplasia and a fibrous cap in the innermost layer of the wall (41,42). A single vSMC from the tunica media can migrate to the tunica intima and clonally gives rise to SMC-derived cells in atherosclerotic plaques (43). In addition, it has been established that vSMCs, contribute to a predominantly large fraction of foam cells in human atheroma and experimental models of atherosclerosis (44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

Injury to the tunica media initiates atherogenesis in the presence of hyperlipidemia

Belhoul-Fakir

Wu²,

Yeow³

et al. 2023

Front. Cardiovasc. Med.

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Background and aimsFatty streaks initiating the formation of atheromatous plaque appear in the tunica intima. The tunica media is not known to be a nidus for lipid accumulation initiating atherogenesis. We assessed changes to the tunica media in response to a micro-injury produced in the pig aorta. In addition, we assessed human carotid endarterectomy plaques for indication of atheroma initiation in the tunica media.MethodsThree healthy landrace female pigs underwent laparotomy to inject autologous blood and create micro-hematomas at 6 sites within the tunica media of the infrarenal abdominal aorta. These pigs were fed a high-fat diet (HFD) for 4–12 weeks. Post-mortem aortas from all pigs, including a control group of healthy pigs, were serially stained to detect lipid deposits, vasa vasora (VV), immune cell infiltration and inflammatory markers, as well as changes to the vascular smooth muscle cell (vSMC) compartment. Moreover, 25 human carotid endarterectomy (CEA) specimens were evaluated for their lipid composition in the tunica media and intima.ResultsHigh lipid clusters, VV density, and immune cell infiltrates were consistently observed at 5 out of 6 injection sites under prolonged hyperlipidemia. The hyperlipidemic diet also affected the vSMC compartment in the tunica media adjacent to the tunica adventitia, which correlated with VV invasion and immune cell infiltration. Analysis of human carotid specimens post-CEA indicated that 32% of patients had significantly greater atheroma in the tunica media than in the arterial intima.ConclusionThe arterial intima is not the only site for atherosclerosis initiation. We show that injury to the media can trigger atherogenesis.

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Section: Discussionmentioning

confidence: 99%

Injury to the tunica media initiates atherogenesis in the presence of hyperlipidemia

Belhoul-Fakir

Wu²,

Yeow³

et al. 2023

Front. Cardiovasc. Med.

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“…(4) We used FFPE samples and not fresh frozen tissue, so it cannot be excluded that RNA degradation may affect accuracy of detection of the target genes. (5) This study had no assessment regarding the temporal change in clonal expansion, and we did not conduct a comparison between early-and late-stage atherosclerosis due to the limitation of sample size. ( 6) Since this study is based on static images of histological sections, we were not able to assess for the migration of SMC in the clonal or nonclonal areas.…”

Section: Clonal Expansion Of Atherosclerosis In Human and Mice Modelsmentioning

confidence: 99%

mentioning

confidence: 99%

“…Whether most SMCs within the intimal plaque of atherosclerotic lesions are of polyclonal or monoclonal origin continues to be the subject of debate and may have important therapeutic implications. [3][4][5] Clonality detection requires a method to mark the lineage of cells retained generation after generation. Phenotypic clonality can be detected by X-chromosome Arterioscler Thromb Vasc Biol.…”

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confidence: 99%

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Clonal Proliferation Within Smooth Muscle Cells in Unstable Human Atherosclerotic Lesions

Kawai,

Sakamoto,

Mokry

et al. 2023

ATVB

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BACKGROUND: Studies in humans and mice using the expression of an X-linked gene or lineage tracing, respectively, have suggested that clones of smooth muscle cells (SMCs) exist in human atherosclerotic lesions but are limited by either spatial resolution or translatability of the model. METHODS: Phenotypic clonality can be detected by X-chromosome inactivation patterns. We investigated whether clones of SMCs exist in unstable human atheroma using RNA in situ hybridization (BaseScope) to identify a naturally occurring 24-nucleotide deletion in the 3′UTR of the X-linked BGN (biglycan) gene, a proteoglycan highly expressed by SMCs. BGN-specific BaseScope probes were designed to target the wild-type or deletion mRNA. Three different coronary artery plaque types (erosion, rupture, and adaptive intimal thickening) were selected from heterozygous females for the deletion BGN. Hybridization of target RNA-specific probes was used to visualize the spatial distribution of mutants. A clonality index was calculated from the percentage of each probe in each region of interest. Spatial transcriptomics were used to identify differentially expressed transcripts within clonal and nonclonal regions. RESULTS: Less than one-half of regions of interest in the intimal plaque were considered clonal with the mean percent regions of interest with clonality higher in the intimal plaque than in the media. This was consistent for all plaque types. The relationship of the dominant clone in the intimal plaque and media showed significant concordance. In comparison with the nonclonal lesions, the regions with SMC clonality had lower expression of genes encoding cell growth suppressors such as CD74, SERF-2 (small EDRK-rich factor 2), CTSB (cathepsin B), and HLA-DPA1, among others. CONCLUSIONS: Our novel approach to examine clonality suggests atherosclerosis is primarily a disease of polyclonally and to a lesser extent clonally expanded SMCs and may have implications for the development of antiatherosclerotic therapies.

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“…A new technique that combines scATAC-seq of mitochondrial RNA with scRNA-seq allows for clonal studies and lineage tracing in human samples [ 46 ]. Further scRNA studies will be needed to unravel the clonality of cells in the vasculature in response to atherosclerosis [ 47 ]. In this context, combining scRNA-seq with single-cell whole genome sequencing will be helpful for detecting somatic mutations that accumulate with aging and might underlie clonal expansion.…”

Section: Single-cell Sequencing In Preclinical Animal Modelsmentioning

confidence: 99%

New Insights into Cerebral Vessel Disease Landscapes at Single-Cell Resolution: Pathogenetic and Therapeutic Perspectives

et al. 2022

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Cerebrovascular diseases are a leading cause of death and disability globally. The development of new therapeutic targets for cerebrovascular diseases (e.g., ischemic, and hemorrhagic stroke, vascular dementia) is limited by a lack of knowledge of the cellular and molecular biology of health and disease conditions and the factors that cause injury to cerebrovascular structures. Here, we describe the role of advances in omics technology, particularly RNA sequencing, in studying high-dimensional, multifaceted profiles of thousands of individual blood and vessel cells at single-cell resolution. This analysis enables the dissection of the heterogeneity of diseased cerebral vessels and their atherosclerotic plaques, including the microenvironment, cell evolutionary trajectory, and immune response pathway. In animal models, RNA sequencing permits the tracking of individual cells (including immunological, endothelial, and vascular smooth muscle cells) that compose atherosclerotic plaques and their alteration under experimental settings such as phenotypic transition. We describe how single-cell RNA transcriptomics in humans allows mapping to the molecular and cellular levels of atherosclerotic plaques in cerebral arteries, tracking individual lymphocytes and macrophages, and how these data can aid in identifying novel immune mechanisms that could be exploited as therapeutic targets for cerebrovascular diseases. Single-cell multi-omics approaches will likely provide the unprecedented resolution and depth of data needed to generate clinically relevant cellular and molecular signatures for the precise treatment of cerebrovascular diseases.

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Emerging Concepts of Vascular Cell Clonal Expansion in Atherosclerosis

Cited by 15 publications

References 109 publications

Injury to the tunica media initiates atherogenesis in the presence of hyperlipidemia

Injury to the tunica media initiates atherogenesis in the presence of hyperlipidemia

Clonal Proliferation Within Smooth Muscle Cells in Unstable Human Atherosclerotic Lesions

New Insights into Cerebral Vessel Disease Landscapes at Single-Cell Resolution: Pathogenetic and Therapeutic Perspectives

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