Senescent cell extracellular vesicles are critical elements restricting cancer recurrence [scRNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1090462 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28411486.fastq.gz | Fastqsanger.gz | |||
| SRR28411487.fastq.gz | Fastqsanger.gz | |||
| SRR28411488.fastq.gz | Fastqsanger.gz | |||
| SRR28411489.fastq.gz | Fastqsanger.gz | |||
| SRR28411490.fastq.gz | Fastqsanger.gz |
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Project description:Senescent cell extracellular vesicles are critical elements restricting cancer recurrence [bulk RNA-seq]
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Project description:Senescent cell extracellular vesicles (senEVs)are novel and underappreciated components of the senescence secretome. To understand the role that senEVs play in inflammatory responses to senescence, we developed and validated a novel engraftment-based senescence model that allowed us to genetically block the release of senEVs in vivo. We found that senEVs orchestrate prompt removal of senescent cells and inhibit tumor recurrence. Recruitment of MHC-II+ antigen presenting cells into the senescence microenvironment was significantly decreased in the absence of senEVs. Inhibition of senEV release changed the primary target of senescent cell signaling from antigen presenting cells to neutrophils. Antigen presenting cells recruited and activated CCR2+ TH17 cells, which in turn inhibited B cell activation. Through multimodal transcriptional and proteomic analysis, we identified 6 ligands that were specific to senEVs, suggesting a role in promoting cell adhesion. Overall, these results indicate that senEVs complement the activity of secreted inflammatory mediators in recruiting and activating distinct immune cell subsets for efficient removal of senescent cells.
2024-12-23 | GSE262141 | GEO
Project description:Senescent cell extracellular vesicles (senEVs)are novel and underappreciated components of the senescence secretome. To understand the role that senEVs play in inflammatory responses to senescence, we developed and validated a novel engraftment-based senescence model that allowed us to genetically block the release of senEVs in vivo. We found that senEVs orchestrate prompt removal of senescent cells and inhibit tumor recurrence. Recruitment of MHC-II+ antigen presenting cells into the senescence microenvironment was significantly decreased in the absence of senEVs. Inhibition of senEV release changed the primary target of senescent cell signaling from antigen presenting cells to neutrophils. Antigen presenting cells recruited and activated CCR2+ TH17 cells, which in turn inhibited B cell activation. Through multimodal transcriptional and proteomic analysis, we identified 6 ligands that were specific to senEVs, suggesting a role in promoting cell adhesion. Overall, these results indicate that senEVs complement the activity of secreted inflammatory mediators in recruiting and activating distinct immune cell subsets for efficient removal of senescent cells.
2024-12-23 | GSE262139 | GEO
Project description:We report small RNA sequencing technology for high-throughput profiling of microRNA content within small extracellular vesicles isolated from nonsenescent and senescent human dermal fibroblasts.
2021-09-16 | GSE184084 | GEO
Project description:Cellular senescence prevents the proliferation of cells at risk for neoplastic transformation. However, the altered secretome of senescent cells can promote the growth of the surrounding cancer cells. Although extracellular vesicles (EVs) have emerged as new players in intercellular communication, their role in the function of senescent cell secretome has been largely unexplored. Here, we show that exosome-like small EVs (sEVs) are important mediators of the pro-tumorigenic function of senescent cells. sEV-associated EphA2 secreted from senescent cells binds to ephrin-A1 that is highly expressed in several types of cancer cells and promotes cell proliferation through EphA2/ephrin-A1 reverse signalling. sEV sorting of EphA2 is increased in senescent cells due to its enhanced phosphorylation resulting from oxidative inactivation of PTP1B phosphatase. Our results demonstrate a novel mechanism of reactive oxygen species (ROS)-regulated cargo sorting into sEVs, which is critical for the potentially deleterious growth-promoting effect of the senescent cell secretome.
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Project description:We report small RNA sequencing technology for high-throughput profiling of microRNA content within small extracellular vesicles isolated from nonsenescent and senescent human umbilical cord mesenchymal stem cells (hUCMSCs)
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Project description:Senescent cells are beneficial for repairing acute tissue damage, but they are harmful when they accumulate in tissues, as occurs with advancing age. Senescence-associated extracellular vesicles (S-EVs) can mediate cell-to-cell communication and export intracellular content to the microenvironment of aging tissues. Here, we studied the uptake of EVs from senescent cells (S-EVs) relative to proliferating cells (P-EVs). Interestingly, P-EVs were readily taken up by other proliferating cells (fibroblasts and cervical cancer cells) while S-EVs were not; by contrast, macrophages selectively engulfed all EVs (P-EVs, S-EVs). We thus investigated the surface proteome (surfaceome) of P-EVs relative to S-EVs derived from cells that had reached senescence via replicative exhaustion, exposure to ionizing radiation, or treatment with etoposide. We discovered that relative to P-EVs, S-EVs from all senescence models were enriched in proteins DPP4, ANXA1, ANXA6, S10AB, AT1A1, and EPHB2. Among them, DPP4 was found to dictate selective uptake by proliferating cells, as ectopic overexpression of DPP4 in HeLa cells rendered DPP-expressing EVs that were no longer taken up by other proliferating cells. We propose that DPP4 on the surface of S-EVs makes these EVs refractory to internalization by proliferating cells, advancing our knowledge of the impact of senescent cells in aging-associated processes.
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Project description:Surfaceome analysis of extracellular vesicles from senescent cells uncovers uptake repressor DPP4
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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:Cellular senescence is a heterogeneous phenotype, driven by diverse effector programs, which result in irreversible growth arrest, DNA damage, production of complex secretome and metabolic reprogramming1,2. Here we show that in liver-specific Setd8-KO mice, after mitogen treatment, a significant number of hepatocytes become senescent, have enlarged nuclei and increased nuclear envelope plasticity. Despite cell cycle arrest, senescent cells in Setd8-deficient mice retain inherent capability to replicate DNA, resulting in endoreduplication-driven chromosomal hyperploidy. Remarkably, the enlarged nuclei had multiple nuclear engulfments progressing to the generation of large intranuclear vesicles surrounded by nuclear lamina. These vesicles had externally-positioned membrane-associated chromatin, contained glycogen, various cytoplasmic proteins, even whole organelles like ER or mitochondria. We term this process “endonucleosis”. Intranuclear vesicles were absent in hepatocytes of Setd8/Atg5 double knockout mice, suggesting that the process requires the canonical autophagy machinery. Endonucleosis and hyperploidization are temporary, early features of senescence. Larger vesicles were split into microvesicles over time and were eventually eliminated, while large nuclei were segregated into smaller ones without mitosis. The results reveal a unique senescence phenotype with several unusual features, such as hyperploidy, endonucleosis and nuclear segregation, all of which are anticipated to function as parts of survival mechanisms to escape necrotic death.
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