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Controlled release of exosomes by AMPK/SREBPs pathway

ABSTRACT: Exosome-like extracellular vesicles (EVs) are very important vesicles for intercellular signal transmission. Although host factors involving exosome-like EV production and release has been reported, the cellular signaling pathway regulating EV production is largely unknown. Here we performed a kinase inhibitor library screening to identify pathways controlling EV’s production. We found a kinase inhibitor, APY0201, which significantly increased EV secretion through upregulation of intracellular sterol synthesis and the volume of intracellular multivesicular bodies (MVBs). APY0201 specifically caused the decrease of AMP-activated protein kinase (AMPK) phosphorylation and activation of sterol regulatory element-binding protein (SREBP1), a pivotal transcription factor of sterol synthesis gene expression. In addition, both AMPK agonist and SREBP inhibitor deteriorate augmented EV production induced by APY0201. Ectopic expression of AMPK and SREBP1 corroborated that AMPK and SREBP1 are two major host factors governing the production of exosome-like EVs. Taken together, we identified that APY0201 is a novel kinase inhibitor targeting AMPK-SREBP1 pathway which is important for EV biogenesis and release. Our findings might pave the way to achievable finely upregulated EV production.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171807 | GEO | 2023/06/01

REPOSITORIES: GEO

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Growth media conditions influence the secretion route and release levels of engineered extracellular vesicles

Project description:Extracellular vesicles (EVs) are nanosized cell-derived vesicles found in all bodily fluids which provide a route of intercellular communication by transmitting biological cargo. While EVs offer promise as therapeutic agents, the molecular mechanisms of EV biogenesis are not yet fully elucidated, in part due to the concurrence of numerous interwoven pathways which give rise to heterogenous EV populations in vitro. The effects of conditions in the cellular environment on EV production are of particular interest. In this study, we utilize a quantifiable EV-engineering approach to investigate how various cell media conditions alter EV production. The presence of serum, exogenous EVs, and other signaling factors in cell media alters EV production on physical, molecular, and transcriptional levels. Further, we demonstrate that exosome biogenesis pathways are the major factors contributing to EV production under optimized conditions. Our findings suggest a novel understanding to the mechanisms underlying EV production in cell culture which can be applied to develop advanced EV production methods.

2021-04-29 | GSE173474 | GEO

Characterization and Small RNA Content of Extracellular Vesicles in Follicular Fluid of Developing Bovine Antral Follicles

Project description:Exosomes and microvesicles (i.e., extracellular vesicles; EVs) have been identified within ovarian follicular fluid, and recent evidence suggests that EVs are able to elicit profound effects on ovarian cell function. While existence of miRNA within EVs has been reported, it remains unknown if EV size and concentration as well as their cargos (i.e., proteins and RNA) change during antral follicle growth. Extracellular vesicles isolated from follicular fluid of small, medium and large bovine follicles were similar in size, while concentration of EVs decreased progressively as follicle size increased. Electron microscopy indicated a highly purified population of the lipid bilayer enclosed vesicles that were enriched in exosome biomarkers including CD81 and Alix. Small RNA sequencing identified a large number of known and novel miRNAs that changed in the EVs of different size follicles. Ingenuity Pathway Analysis (IPA) indicated that miRNA abundant in small follicle EV preparations were associated with cell proliferation pathways, while those miRNA abundant in large follicle preparations were related to inflammatory response pathways. These studies are the first to demonstrate that EVs change in their levels and makeup during antral follicle development and point to the potential for a unique vesicle-mediated cell-to-cell communication network within the ovarian follicle. Examination of small RNA population in bovine follicular fluid extracellular vesicles isolated from antral follicles

2016-02-09 | E-GEOD-74879 | biostudies-arrayexpress

Crosstalk between the effects of extracellular vesicles (Evs) and TNF on U937 human monocyte cell line

Project description:Under physiological conditions, extracellular vesicles (EVs) are present simultaneously in the extracellular compartment together with cytokines. Thus, we hypothesized that EVs in combination with cytokines induce different responses of monocyte cells compared to EVs or cytokines alone. Human monocyte U937 cells were incubated with EV-containing or EV-free CCRF human T-cell supernatant, with or without the addition of TNF. U937 cells cultured in EV-free supernatant, supernatant containing CCRF t-cell derived EVs, TNF or both. Each treatment option was measured in 3 replicates.

2013-06-19 | E-GEOD-47897 | biostudies-arrayexpress

Comparative transcriptomic analysis of human and Drosophila extracellular vesicles reveals extensive conservation

Project description:Extracellular vesicles (EVs) are membrane-enclosed nanoparticles containing specific repertoires of genetic material. In mammals, EVs can mediate the horizontal transfer of various cargos and signaling molecules, notably miRNA and mRNA species. Whether this form of intercellular communication prevails in other metazoans remains unclear. Here, we report the first parallel comparative morphologic and transcriptomic characterization of EVs from Drosophila and human cellular models. Electronic microscopy revealed that Drosophila, like human cells release exosome-like EVs with diameter ranging from 30 to 200 nm, which contain complex populations of transcripts. RNA-seq identified abundant ribosomal RNA pseudogenes and retrotransposons in human and Drosophila EVs. Vault RNAs and Y RNAs abounded in human samples, whereas small nucleolar RNAs involved in pseudouridylation were most prevalent in Drosophila EVs. Numerous mRNAs were identified, largely consisting of exonic sequences displaying full-length read coverage and enriched for translation and electronic transport chain functions. By analogy with human systems, these extensive similarities suggest that EVs could also enable RNA-mediated intercellular communication in Drosophila. We performed RNA-seq on extracellular vesicles purified from of human and Drosophila cell line cultures. S2R+ and D17 Drosophila EVs were analyzed, along with human A431 and HepG2 EVs. No ribosomal RNA depletion or polyA selection was performed on EV samples. For comparative analyses, we also analyzed total cellular RNA from Drosophila D17 and human HepG2. Ribodepletion was performed on cellular samples.

2016-06-15 | E-GEOD-76173 | biostudies-arrayexpress

Proteomic signatures of extracellular vesicles secreted by non-mineralizing and mineralizing human osteoblasts and stimulation of tumor cell growth

Project description:Beyond forming bone, osteoblasts play pivotal roles in various biological processes, including hematopoiesis and bone metastasis. Extracellular vesicles (EVs) have recently been implicated in intercellular communication via transfer of proteins and nucleic acids between cells. Here, we focused on the proteomic characterization of non-mineralizing (NMOBs) and mineralizing (MOBs) human osteoblast (SV-HFOs) EVs and investigated their effect on human prostate cancer (PC3) cells by microscopic, proteomic and gene expression analyses. Proteomic analysis showed that 97% of the proteins were shared among NMOB and MOB EVs, and 30% were novel osteoblast-specific EV proteins. Label-free quantification demonstrated mineralization stage-dependent five-fold enrichment of 59 and 451 EV proteins in NMOBs and MOBs, respectively. Interestingly, bioinformatic analyses of the osteoblast EV proteomes and EV-regulated prostate cancer gene expression profiles showed that they converged on pathways involved in cell survival and growth. This was verified by in vitro proliferation assays where osteoblast EV uptake led to two-fold increase in PC3 cell growth compared to cell-free culture medium-derived vesicle controls. Our findings elucidate the mineralization stage-specific protein content of osteoblast-secreted EVs, show a novel way by which osteoblasts communicate with prostate cancer, and open up innovative avenues for therapeutic intervention. PC3 cells were treated with extracellular vesicles from non-mineralizing and mineralizing SV-HFOs for three different incubation times (4hrs, 24hrs, 48hr)

2014-10-28 | E-GEOD-56172 | biostudies-arrayexpress

A novel method of spontaneously-released extracellular vesicle isolation from brain

Project description:Extracellular Vesicles (EVs) exhibit great potential in for brain disease diagnositics and treatment, representing a valuable tool in the new era of pPrecision medicine which demands high-quality human biospecimens. However, current brain exosome EV isolation approaches rely on its tissue dissociation, which may can contaminate the exosome EV fractions with immature intralumenalcellular vesicles that wcould otherwise be targeted for endolysosomal degradation. Hereby, we present an efficient exosome purification method that captures a more physiologically relevant EV population exosome-enriched extracellular vesicles (EVs) spontaneously released by mouse and human brain tissue, representing a more physiologically relevant exosome EV population.

2023-08-03 | PXD026712 | Pride

Characteristics of Human and Microbiome RNA Profiles in Saliva

Project description:Saliva is a convenient non-invasive source of liquid biopsy to monitor human health and diagnose diseases. In particular, extracellular vesicles (EVs) in saliva can potentially reveal clinically relevant information for systemic health. Recent studies have shown that RNA in saliva EVs could be exploited as biomarkers for disease diagnosis. However, there is no standardized protocol for profiling RNA in saliva EV nor clear guideline on selecting saliva fractions for biomarker analysis. To address these issues, we established a robust protocol for small RNA profiling from fractionated saliva. With this method, we performed comprehensive small RNA sequencing of four saliva fractions, including cell-free saliva (CFS), EV-depleted saliva (EV-D), exosome (EXO), and microvesicle (MV) from ten healthy volunteers. Methods: To address these issues, we established a robust protocol for small RNA profiling from fractionated saliva. With this method, we performed comprehensive small RNA sequencing of four saliva fractions, including cell-free saliva (CFS), EV-depleted saliva (EV-D), exosome (EXO), and microvesicle (MV) from ten healthy volunteers.

2023-01-07 | GSE222014 | GEO

Exosomes dependent immune surveillance at the metastatic niche requires BAG6

Project description:Mice were intravenously injected with extracellular vesicles (EVs) isolated from B16V wt (n=3) or BAG6KO (n=3) cells or with PBS (n=3) as a control for 4 weeks on a weekly basis. Since B-16V melanoma cells colonise the lung upon intravenous injection and referring to current literature, we hypothesise that melanoma EVs alter the (immune-) microenvironment of the lung to prepare a pre-metastatic niche. Based on current literature and own previous experiments identifying BAG6 as an immunoregulatory protein that is also involved in the biogenesis of EVs, we are particularly interested in differences between the immune signature upon wt EV treatment compared to BAG6KO EV treatment.

2019-11-29 | E-MTAB-7119 | biostudies-arrayexpress

Characterization and Small RNA Content of Extracellular Vesicles in Follicular Fluid of Developing Bovine Antral Follicles

2016-02-09 | GSE74879 | GEO

Osteoblasts secrete miRNA-containing extracellular vesicles that enhance expansion of human umbilical cord blood cells

Project description:Osteolineage cells represent one of the critical bone marrow niche components that support maintenance of hematopoietic stem and progenitor cells (HSPCs). Recent studies demonstrate that extracellular vesicles (EVs) regulate stem cell development via horizontal transfer of bioactive cargo, including microRNAs (miRNAs). Here, we characterize the miRNA profile of EVs secreted by human osteoblasts and study their biological effect of on human umbilical cord blood-derived CD34+ HSPCs by sequencing, gene expression and biochemical analyses. Using next-generation sequencing we show that osteoblast-derived EVs contain highly abundant miRNAs specifically enriched in EVs, including critical regulators of hematopoietic proliferation (e.g., miR-29a). EV treatment of CD34+ HSPCs alters the expression of candidate miRNA targets, such as HBP1, BCL2 and PTEN. Furthermore, EVs enhance proliferation of CD34+ cells and their immature subsets in growth factor-driven ex vivo expansion cultures. Importantly, EV-expanded cells retain their differentiation capacity in vitro and show successful engraftment in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice in vivo. These discoveries reveal a novel osteoblast-derived EV-mediated mechanism for regulation of HSPC proliferation and warrant consideration of EV-miRNAs for the development of expansion strategies to treat hematological disorders.

2016-10-05 | E-MTAB-4560 | biostudies-arrayexpress

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