Single-cell and spatial transcriptomics uncovers the role of senescent vascular cells in pathological arterial remodeling during murine atherosclerosis
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PROVIDER: PRJNA999750 | ENA |
REPOSITORIES: ENA
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Project description:Studying cardiovascular senescence is crucial in understanding the diverse manifestations of disease-related changes in the cardiovascular system and their implications for overall health and disease. To systematically investigate the heterogeneity of senescent vascular cells in atherosclerosis, we employed the senescence reporter mouse p16TdTomato+/-, injected with an adeno-associated virus expressing PCSK9 to induce atherosclerosis when fed a high-fat diet (HFD). We then treated this mouse with the senolytic drug ABT-737 or vehicle. Whole-aorta single-cell RNA-sequencing (scRNA-seq) and Gene Set Enrichment Analysis (GSEA) using the SenMayo panel, uncovered 10 cell clusters displaying increased senescent features that were reduced by treatment with ABT-737. Interestingly, these clusters do not express ‘classical’ senescence markers such as p16 and p21, but were senescent based on SenMayo GSEA, indicating that the senescence transcriptomic signature in this niche requires deeper characterization. Using unbiased subclustering of the top four potentially senescent clusters, we identified subsets of cells increasing by HFD and reduced by ABT-737 treatment. Accordingly, unique transcripts associated with each subpopulation, such as Spp1, Ctsb, and Tnfrsf11b, implicated these cells in senescence-related signaling pathways. We then validated these findings by spatial transcriptomic profiling, locating senescent cells in the cap and core of brachiocephalic arteries from atherosclerotic mice. Our results uncover a new vascular-specific transcriptomic signature that may be exploited for therapeutic targeting in age-related vascular diseases.
2024-07-28 | GSE239602 | GEO
Project description:Senescent cells suppress innate VSMC repair functions in atherosclerosis
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Project description:Intermittent childhood hyperlipidaemia alters resident arterial macrophages and accelerates atherosclerosis
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Project description:Intermittent childhood hyperlipidaemia alters resident arterial macrophages and accelerates atherosclerosis
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Project description:The development of atherosclerosis, a chronic disease characterized by the buildup of plaque in arterial walls, involves the contribution of vascular smooth muscle cells (SMCs) and SMC-derived cells. To better understand the specific role of SMCs in atherosclerosis, a transgenic mouse line expressing EGFP-tagged ribosomal protein L10a (EGFP-L10a) under the SMC-specific αSMA promoter (SMCTRAP mice) was developed, enabling translating ribosome affinity purification followed by sequencing (TRAP-Seq). SMCTRAP mice were crossed with an atherosclerosis model (SMCTRAP-Athero mice). Using TRAP-Seq and bulk RNA-Seq, the aortas of 15-month-old SMCTRAP and SMCTRAP-Athero mice were analyzed to identify atherosclerosis-induced changes in the profiles of SMC ribosome-associated RNA. The results showed high enrichment of known SMC-specific genes in the TRAP fraction, indicating the specificity of the construct. The intersection of SMC-specific genes identified by TRAP-Seq, and atherosclerosis-induced genes identified by bulk RNA-Seq revealed the contribution of SMCs to the expression of several known disease-induced genes, as well as the identification of previously unlinked genes in atherosclerosis that warrant further investigation. These findings provide new insights into the role of SMCs in atherosclerosis and may offer potential targets for future treatments of this chronic disease.
2024-02-08 | GSE225424 | GEO
Project description:Atherosclerosis represents an age-related disease, which remains one of the leading cause of deaths in developed countries. It begins with a local deposition of lipid in the innermost part of the artery – intima. Thereafter a number of immune cells are attracted and infiltrate into the artery wall, where, together with endothelia and smooth muscle cells, form an atherosclerotic plaque (Libby, 2008). Thus, atherosclerosis is considered as an inflammatory disease, characterized by intense immunological activity (Libby P, 2012). One of the main risk factor for atherosclerosis is aging. It was demonstrated that there is an accumulation of senescent cells within atherosclerotic plaque (..). Accordingly, vascular smooth muscle cells (VSMCs) derived from the lesion demonstrate a phenotype characteristic for senescent cells: diminished proliferative potential, shorter telomeres, increased number of DNA damage and upregulation of SA-β-gal activity (Gorenne, 2006; Matthes, 2006, Mahomoudi, 2008). Accumulation of senescent VSMCs within the area of plaque development promotes its instability due to lack of proliferation and impaired production of extracellular matrix, both leading to weakening of fibrous cap (Gorenne, 2006). This has been further confirmed by the observation, that elimination of senescent cells in the atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr-/-) mice slowed down the disease progression (27789842). One of the most important feature of senescent cells, that has the biggest impact on tissue microenvironment, is their ability to secrete a number of cytokines, chemokines, matrix metalloproteinases and growth factors collectively known as the Senescence Associated Secretory Phenotype (SASP) (20078217, 28165648). Apart from soluble factors, senescent cells secret also an increased number of extracellular vesicles (EVs), research of which has only recently begun (32461143). EVs are small membranous vesicles that can be categorized based on their size and origin, into: exosomes, microvesicles and apoptotic bodies. EVs play crucial role as carriers of proteins, different types of RNA and DNA, lipids and metabolites that, take part in intercellular communication (23420871). They were shown to participate in many physiological but also pathological conditions. Studies performed over the last decade proved that EVs affect atherosclerosis progression at different stages by several distinct mechanisms (as reviewed by Knokhot, 2020, 33261815). The increased concentrations of EVs have been found in plasma of patients suffering from cardiovascular diseases as well as in atherosclerotic plaque itself (Yin, 2015, 26142082; Rautou, 2011, 21852557). However, the role of EVs derived from senescent cells in atherosclerosis, particularly in the context of the plaque development, remains unknown. The functioning of immune cells within atherosclerotic plaque is modulated by local milieu. Thus, senescent cells present in the lesion can influence plaque development by non-cell autonomous mechanism. Indeed, recently it was demonstrated that SASP factors secreted by senescent VSMCs promote recruitment of monocytes, induce expression of adhesion receptors on endothelial cells and activate adjacent normal VSMCs, promoting inflammation in the plaque (Gardner, 2015). However, the role of EVs in this context has not been studied. Thus, we have undertaken research aimed at investigating the role of senescent cell derived EVs on immune cells activity. To this end, we isolated and characterized the EVs secreted by human VSMCs undergoing senescence. We performed unbiased quantitative proteomic analysis of both soluble and insoluble SASP components. Moreover, we analyzed the influence of EVs derived from senescent and non-senescent cells on T lymphocytes and monocytes. Altogether our studies revealed that EVs produced by senescent VSMCs strengthen inflammatory response of the immune cells, what would have a tremendous significance in atherosclerotic plaque development.
2022-09-08 | PXD030955 | Pride
Project description:Single-cell transcriptomic analysis uncovers diverse and dynamic senescent cell populations
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Project description:Epigenome-wide profiling uncovers novel pathway networks in human pulmonary arterial hypertension
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Project description:Developmental modeling of hepatogenesis using obese iPSCs-hepatocyte differentiation uncovers pathological features
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Project description:Nitric oxide helps to prevent endothelial dysfunction and senescence. This study aimed to define genomic and proteomic changes in cultured porcine senescent endothelial cells and their resemblance with those observed in regenerated endothelial cells. Senescent endothelial cells were produced by passaging primary porcine coronary arterial endothelial cells until passage four. The protein presence of endothelial nitric oxide synthase, cyclic GMP levels [basal and during stimulation (bradykinin and A23187)], were reduced. The mRNA expression level was measured by microarray assays. Genes related to oxidative stress [superoxide dismutase (MnSOD), glutathione peroxidase 3, glutathione S-transferase M1] were downregulated, extracellular matrix components (type III collagen, thrombospondin 1 and 3, transforming growth factor beta) upregulated and nuclear factor kappa B (NFKB)-signaling pathway [IkappaB, TNF receptor-associated factor 1 and 5 (TRAF1 and 5)] activated in senescent cells. The differential gene expression of MnSOD and TRAF5 was confirmed at the protein level by Western blotting and biochemical assay (MnSOD). The basal and stimulated (by tumor necrosis factor-alpha) levels of NFKB were augmented as demonstrated by electrophoretic mobility shift assay. In summary, cultured senescent endothelial cells exhibit reduced nitric oxide production, and decreased antioxidative, proliferative capacities, augmented expression of extracellular matrix components and activation of NFKB. These molecular changes do not exactly mimick those occurring during endothelial regeneration in vivo. Keywords: disease state comparison
2007-09-08 | GSE8974 | GEO