| 1. |
- Bandeira, Elga, et al.
(författare)
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Effects of mesenchymal stem cell-derived nanovesicles in experimental allergic airway inflammation
- 2023
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Allergic asthma is associated with airflow obstruction and hyper-responsiveness that arises from airway inflammation and remodeling. Cell therapy with mesenchymal stem cells (MSC) has been shown to attenuate inflammation in asthma models, and similar effects have recently been observed using extracellular vesicles (EV) obtained from these cells. Biologically functional vesicles can also be artificially generated from MSC by extruding cells through membranes to produce EV-mimetic nanovesicles (NV). In this study, we aimed to determine the effects of different MSC-derived vesicles in a murine model of allergic airway inflammation.Methods EV were obtained through sequential centrifugation of serum-free media conditioned by human bone marrow MSC for 24 h. NV were produced through serial extrusion of the whole cells through filters. Both types of vesicles underwent density gradient purification and were quantified through nanoparticle tracking analysis. C57BL/6 mice were sensitized to ovalbumin (OVA, 8 mu g), and then randomly divided into the OVA group (intranasally exposed to 100 mu g OVA for 5 days) and control group (exposed to PBS). The mice were then further divided into groups that received 2 x 10(9) EV or NV (intranasally or intraperitoneally) or PBS immediately following the first OVA exposure.Results Administration of EV and NV reduced cellularity and eosinophilia in bronchoalveolar lavage (BAL) fluid in OVA-sensitized and OVA-exposed mice. In addition, NV treatment resulted in decreased numbers of inflammatory cells within the lung tissue, and this was associated with lower levels of Eotaxin-2 in both BAL fluid and lung tissue. Furthermore, both intranasal and systemic administration of NV were effective in reducing inflammatory cells; however, systemic delivery resulted in a greater reduction of eosinophilia in the lung tissue.Conclusions Taken together, our results indicate that MSC-derived NV significantly reduce OVA-induced allergic airway inflammation to a level comparable to EV. Thus, cell-derived NV may be a novel EV-mimetic therapeutic candidate for treating allergic diseases such as asthma.
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| 2. |
- Kim, Dae-Kyum, et al.
(författare)
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EVpedia: A Community Web Portal for Extracellular Vesicles Research
- 2015
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 31:6, s. 933-939
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Tidskriftsartikel (refereegranskat)abstract
- Motivation: Extracellular vesicles (EVs) are spherical bilayered proteolipids, harboring various bioactive molecules. Due to the complexity of the vesicular nomenclatures and components, online searches for EV-related publications and vesicular components are currently challenging. Results: We present an improved version of EVpedia, a public database for EVs research. This community web portal contains a database of publications and vesicular components, identification of orthologous vesicular components, bioinformatic tools and a personalized function. EVpedia includes 6879 publications, 172 080 vesicular components from 263 high-throughput datasets, and has been accessed more than 65 000 times from more than 750 cities. In addition, about 350 members from 73 international research groups have participated in developing EVpedia. This free web-based database might serve as a useful resource to stimulate the emerging field of EV research.
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| 3. |
- Kim, Dae-Kyum, et al.
(författare)
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EVpedia: an integrated database of high-throughput data for systemic analyses of extracellular vesicles.
- 2013
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Ingår i: Journal of extracellular vesicles. - : Wiley. - 2001-3078. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- Secretion of extracellular vesicles is a general cellular activity that spans the range from simple unicellular organisms (e.g. archaea; Gram-positive and Gram-negative bacteria) to complex multicellular ones, suggesting that this extracellular vesicle-mediated communication is evolutionarily conserved. Extracellular vesicles are spherical bilayered proteolipids with a mean diameter of 20-1,000 nm, which are known to contain various bioactive molecules including proteins, lipids, and nucleic acids. Here, we present EVpedia, which is an integrated database of high-throughput datasets from prokaryotic and eukaryotic extracellular vesicles. EVpedia provides high-throughput datasets of vesicular components (proteins, mRNAs, miRNAs, and lipids) present on prokaryotic, non-mammalian eukaryotic, and mammalian extracellular vesicles. In addition, EVpedia also provides an array of tools, such as the search and browse of vesicular components, Gene Ontology enrichment analysis, network analysis of vesicular proteins and mRNAs, and a comparison of vesicular datasets by ortholog identification. Moreover, publications on extracellular vesicle studies are listed in the database. This free web-based database of EVpedia (http://evpedia.info) might serve as a fundamental repository to stimulate the advancement of extracellular vesicle studies and to elucidate the novel functions of these complex extracellular organelles.
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| 4. |
- Park, Kyong-Su, et al.
(författare)
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Mesenchymal stromal cell-derived nanovesicles ameliorate bacterial outer membrane vesicle-induced sepsis via IL-10.
- 2019
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Ingår i: Stem cell research & therapy. - : Springer Science and Business Media LLC. - 1757-6512. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Sepsis remains a source of high mortality in hospitalized patients despite proper antibiotic approaches. Encouragingly, mesenchymal stromal cells (MSCs) and their produced extracellular vesicles (EVs) have been shown to elicit anti-inflammatory effects in multiple inflammatory conditions including sepsis. However, EVs are generally released from mammalian cells in relatively low amounts, and high-yield isolation of EVs is still challenging due to a complicated procedure. To get over these limitations, vesicles very similar to EVs can be produced by serial extrusions of cells, after which they are called nanovesicles (NVs). We hypothesized that MSC-derived NVs can attenuate the cytokine storm induced by bacterial outer membrane vesicles (OMVs) in mice, and we aimed to elucidate the mechanism involved.NVs were produced from MSCs by the breakdown of cells through serial extrusions and were subsequently floated in a density gradient. Morphology and the number of NVs were analyzed by transmission electron microscopy and nanoparticle tracking analysis. Mice were intraperitoneally injected with Escherichia coli-derived OMVs to establish sepsis, and then injected with 2×109 NVs. Innate inflammation was assessed in peritoneal fluid and blood through investigation of infiltration of cells and cytokine production. The biodistribution of NVs labeled with Cy7 dye was analyzed using near-infrared imaging.Electron microscopy showed that NVs have a nanometer-size spherical shape and harbor classical EV marker proteins. In mice, NVs inhibited eye exudates and hypothermia, signs of a systemic cytokine storm, induced by intraperitoneal injection of OMVs. Moreover, NVs significantly suppressed cytokine release into the systemic circulation, as well as neutrophil and monocyte infiltration in the peritoneum. The protective effect of NVs was significantly reduced by prior treatment with anti-interleukin (IL)-10 monoclonal antibody. In biodistribution study, NVs spread to the whole mouse body and localized in the lung, liver, and kidney at 6h.Taken together, these data indicate that MSC-derived NVs have beneficial effects in a mouse model of sepsis by upregulating the IL-10 production, suggesting that artificial NVs may be novel EV-mimetics clinically applicable to septic patients.
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| 5. |
- Svennerholm, Kristina, 1981, et al.
(författare)
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Escherichia coli outer membrane vesicles can contribute to sepsis induced cardiac dysfunction.
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Sepsis induced cardiac dysfunction (SIC) is a severe complication to sepsis which significantly worsens patient outcomes. It is known that bacteria have the capacity to release outer membrane vesicles (OMVs), which are nano-sized bilayered vesicles composed of lipids and proteins, that can induce a fatal inflammatory response. The aim of this study was to determine whether OMVs from a uropathogenic Escherichia coli strain can induce cardiac dysfunction, and to elucidate any mechanisms involved. OMVs induced irregular Ca2+ oscillations with a decreased frequency in cardiomyocytes through recordings of intracellular Ca2+ dynamics. Mice were intraperitoneally injected with bacteria-free OMVs, which resulted in increased concentration of pro-inflammatory cytokine levels in blood. Cytokines were increased in heart lysates, and OMVs could be detected in the heart after OMVs injection. Troponin T was significantly increased in blood, and echocardiography showed increased heart wall thickness as well as increased heart rate. This study shows that E. coli OMVs induce cardiac injury in vitro and in vivo, in the absence of bacteria, and may be a causative microbial signal in SIC. The role of OMVs in clinical disease warrant further studies, as bacterial OMVs in addition to live bacteria may be good therapeutic targets to control sepsis.
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| 6. |
- Crescitelli, Rossella, 1985, et al.
(författare)
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Subpopulations of extracellular vesicles from human metastatic melanoma tissue identified by quantitative proteomics after optimized isolation
- 2020
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Ingår i: Journal of Extracellular Vesicles. - : Wiley. - 2001-3078. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The majority of extracellular vesicle (EV) studies conducted to date have been performed on cell lines with little knowledge on how well these represent the characteristics of EVs in vivo. The aim of this study was to establish a method to isolate and categorize subpopulations of EVs isolated directly from tumour tissue. First we established an isolation protocol for subpopulations of EVs from metastatic melanoma tissue, which included enzymatic treatment (collagenase D and DNase). Small and large EVs were isolated with differential ultracentrifugation, and these were further separated into high and low-density (HD and LD) fractions. All EV subpopulations were then analysed in depth using electron microscopy, Bioanalyzer (R), nanoparticle tracking analysis, and quantitative mass spectrometry analysis. Subpopulations of EVs with distinct size, morphology, and RNA and protein cargo could be isolated from the metastatic melanoma tissue. LD EVs showed an RNA profile with the presence of 18S and 28S ribosomal subunits. In contrast, HD EVs had RNA profiles with small or no peaks for ribosomal RNA subunits. Quantitative proteomics showed that several proteins such as flotillin-1 were enriched in both large and small LD EVs, while ADAM10 were exclusively enriched in small LD EVs. In contrast, mitofilin was enriched only in the large EVs. We conclude that enzymatic treatments improve EV isolation from dense fibrotic tissue without any apparent effect on molecular or morphological characteristics. By providing a detailed categorization of several subpopulations of EVs isolated directly from tumour tissues, we might better understand the function of EVs in tumour biology and their possible use in biomarker discovery.
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| 7. |
- Cvjetkovic, Aleksander, et al.
(författare)
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Detailed Analysis of Protein Topology of Extracellular Vesicles–Evidence of Unconventional Membrane Protein Orientation
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs) are important mediators of intercellular communication that change the recipient cell by shuttling lipids, RNA, or protein cargo between cells. Here, we investigate the topology of the protein cargo found in EVs, as this topology can fundamentally influence the biological effects of EVs. A multiple proteomics approach, combining proteinase treatment and biotin tagging, shows that many proteins of cytosolic origin are localized on the surface of EVs. A detailed analysis of the EV proteome at the peptide level revealed that a number of EV membrane proteins are present in a topologically reversed orientation compared to what is annotated. Two examples of such proteins, SCAMP3 and STX4, were confirmed to have a reversed topology. This reversed typology was determined using flow cytometry and fluorescent microscopy with antibodies directed toward their cytoplasmic epitopes. These results describe a novel workflow to define the EV proteome and the orientation of each protein, including membrane protein topology. These data are fundamentally important to understanding the EV proteome and required to fully explain EV biogenesis as well as biological function in recipient cells.
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| 8. |
- Hwang, D. W., et al.
(författare)
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Noninvasive imaging of radiolabeled exosome-mimetic nanovesicle using Tc-99m-HMPAO
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Exosomes known as nano-sized extracellular vesicles attracted recent interests due to their potential usefulness in drug delivery. Amid remarkable advances in biomedical applications of exosomes, it is crucial to understand in vivo distribution and behavior of exosomes. Here, we developed a simple method for radiolabeling of macrophage-derived exosome-mimetic nanovesicles (ENVs) with Tc-99m-HMPAO under physiologic conditions and monitored in vivo distribution of Tc-99m-HMPAO-ENVs using SPECT/CT in living mice. ENVs were produced from the mouse RAW264.7 macrophage cell line and labeled with Tc-99m-HMPAO for 1 hr incubation, followed by removal of free Tc-99m-HMPAO. SPECT/CT images were serially acquired after intravenous injection to BALB/c mouse. When ENVs were labeled with Tc-99m-HMPAO, the radiochemical purity of Tc-99m-HMPAO-ENVs was higher than 90% and the expression of exosome specific protein (CD63) did not change in Tc-99m-HMPAO-ENVs. Tc-99m-HMPAOENVs showed high serum stability (90%) which was similar to that in phosphate buffered saline until 5 hr. SPECT/CT images of the mice injected with Tc-99m-HMPAO-ENVs exhibited higher uptake in liver and no uptake in brain, whereas mice injected with Tc-99m-HMPAO showed high brain uptake until 5 hr. Our noninvasive imaging of radiolabeled-ENVs promises better understanding of the in vivo behavior of exosomes for upcoming biomedical application.
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| 9. |
- Jang, Su Chul, 1984, et al.
(författare)
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Bioinspired Exosome-Mimetic Nanovesicles for Targeted Delivery of Chemotherapeutics to Malignant Tumors.
- 2013
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Ingår i: ACS nano. - : American Chemical Society (ACS). - 1936-086X .- 1936-0851. ; 7:9, s. 7698-7710
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Tidskriftsartikel (refereegranskat)abstract
- Exosomes, the endogenous nanocarriers that can deliver biological information between cells, were recently introduced as new kind of drug delivery system. However, mammalian cells release relatively low quantities of exosomes, and purification of exosomes is difficult. Here, we developed bioinspired exosome-mimetic nanovesicles that deliver chemotherapeutics to the tumor tissue after systemic administration. The chemotherapeutics-loaded nanovesicles were produced by the breakdown of monocytes or macrophages using a serial extrusion through filters with diminishing pore sizes (10, 5, and 1 μm). These cell-derived nanovesicles have similar characteristics with the exosomes but have 100-fold higher production yield. Furthermore, the nanovesicles have natural targeting ability of cells by maintaining the topology of plasma membrane proteins. In vitro, chemotherapeutic drug-loaded nanovesicles induced TNF-α-stimulated endothelial cell death in a dose-dependent manner. In vivo, experiments in mice showed that the chemotherapeutic drug-loaded nanovesicles traffic to tumor tissue and reduce tumor growth without the adverse effects observed with equipotent free drug. Furthermore, compared with doxorubicin-loaded exosomes, doxorubicin-loaded nanovesicles showed similar in vivo antitumor activity. However, doxorubicin-loaded liposomes that did not carry targeting proteins were inefficient in reducing tumor growth. Importantly, removal of the plasma membrane proteins by trypsinization eliminated the therapeutic effects of the nanovesicles both in vitro and in vivo. Taken together, these studies suggest that the bioengineered nanovesicles can serve as novel exosome-mimetics to effectively deliver chemotherapeutics to treat malignant tumors.
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| 10. |
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| 11. |
- Jang, Su Chul, 1984, et al.
(författare)
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Mitochondrial protein enriched extracellular vesicles discovered in human melanoma tissues can be detected in patient plasma
- 2019
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Ingår i: Journal of Extracellular Vesicles. - : Wiley. - 2001-3078. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs), including exosomes and microvesicles, are secreted from all cells, and convey messages between cells in health and disease. However, the diversity of EV subpopulations is only beginning to be explored. Since EVs have been implicated in tumour microenvironmental communication, we started to determine the diversity of EVs specifically in this tissue. To do this, we isolated EVs directly from patient melanoma metastatic tissues. Using EV membrane isolation and mass spectrometry analysis, we discovered enrichment of mitochondrial membrane proteins in the melanoma tissue-derived EVs, compared to non-melanoma-derived EVs. Interestingly, two mitochondrial inner membrane proteins MT-CO2 (encoded by the mitochondrial genome) and COX6c (encoded by the nuclear genome) were highly prevalent in the plasma of melanoma patients, as well as in ovarian and breast cancer patients. Furthermore, this subpopulation of EVs contains active mitochondrial enzymes. In summary, tumour tissues are enriched in EVs with mitochondrial membrane proteins and these mitochondrial membrane proteins can be detected in plasma and are increased in melanoma, ovarian cancer as well as breast cancer.
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| 12. |
- Karimi, Nasibeh, et al.
(författare)
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Detailed analysis of the plasma extracellular vesicle proteome after separation from lipoproteins
- 2018
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Ingår i: Cellular and Molecular Life Sciences. - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 75:15, s. 2873-2886
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Tidskriftsartikel (refereegranskat)abstract
- The isolation of extracellular vesicles (EVs) from blood is of great importance to understand the biological role of circulating EVs and to develop EVs as biomarkers of disease. Due to the concurrent presence of lipoprotein particles, however, blood is one of the most difficult body fluids to isolate EVs from. The aim of this study was to develop a robust method to isolate and characterise EVs from blood with minimal contamination by plasma proteins and lipoprotein particles. Plasma and serum were collected from healthy subjects, and EVs were isolated by size-exclusion chromatography (SEC), with most particles being present in fractions 8-12, while the bulk of the plasma proteins was present in fractions 11-28. Vesicle markers peaked in fractions 7-11; however, the same fractions also contained lipoprotein particles. The purity of EVs was improved by combining a density cushion with SEC to further separate lipoprotein particles from the vesicles, which reduced the contamination of lipoprotein particles by 100-fold. Using this novel isolation procedure, a total of 1187 proteins were identified in plasma EVs by mass spectrometry, of which several proteins are known as EV-associated proteins but have hitherto not been identified in the previous proteomic studies of plasma EVs. This study shows that SEC alone is unable to completely separate plasma EVs from lipoprotein particles. However, combining SEC with a density cushion significantly improved the separation of EVs from lipoproteins and allowed for a detailed analysis of the proteome of plasma EVs, thus making blood a viable source for EV biomarker discovery.
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| 13. |
- Lázaro-Ibáñez, Elisa, et al.
(författare)
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Distinct prostate cancer-related mRNA cargo in extracellular vesicle subsets from prostate cell lines
- 2017
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Ingår i: Bmc Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 17:92
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multiple types of extracellular vesicles (EVs), including microvesicles (MVs) and exosomes (EXOs), are released by all cells constituting part of the cellular EV secretome. The bioactive cargo of EVs can be shuffled between cells and consists of lipids, metabolites, proteins, and nucleic acids, including multiple RNA species from non-coding RNAs to messenger RNAs (mRNAs). In this study, we hypothesized that the mRNA cargo of EVs could differ based on the EV cellular origin and subpopulation analyzed. Methods: We isolated MVs and EXOs from PC-3 and LNCaP prostate cancer cells by differential centrifugation and compared them to EVs derived from the benign PNT2 prostate cells. The relative mRNA levels of 84 prostate cancer-related genes were investigated and validated using quantitative reverse transcription PCR arrays. Results: Based on the mRNA abundance, MVs rather than EXOs were enriched in the analyzed transcripts, providing a snapshot of the tumor transcriptome. LNCaP MVs specifically contained significantly increased mRNA levels of NK3 Homeobox 1 (NKX3-1), transmembrane protease serine 2 (TMPRSS2), and tumor protein 53 (TP53) genes, whereas PC-3 MVs carried increased mRNA levels of several genes including, caveolin-2 (CAV2), glutathione S-transferase pi 1 (GSTP1), pescadillo ribosomal biogenesis factor 1 (PES1), calmodulin regulated spectrin associated protein 1 (CAMSAP1), zinc-finger protein 185 (ZNF185), and others compared to PNT2 MVs. Additionally, ETS variant 1 (ETV1) and fatty acid synthase (FASN) mRNAs identified in LNCaP-and PC-3-derived MVs highly correlated with prostate cancer progression. Conclusions: Our study provides new understandings of the variability of the mRNA cargo of MVs and EXOs from different cell lines despite same cancer origin, which is essential to better understand the the proportion of the cell transcriptome that can be detected within EVs and to evaluate their role in disease diagnosis.
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| 14. |
- Lázaro-Ibáñez, Elisa, et al.
(författare)
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DNA analysis of low- and high-density fractions defines heterogeneous subpopulations of small extracellular vesicles based on their DNA cargo and topology
- 2019
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Ingår i: Journal of Extracellular Vesicles. - : Wiley. - 2001-3078. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles have the capacity to transfer lipids, proteins, and nucleic acids between cells, thereby influencing the recipient cell's phenotype. While the role of RNAs in EVs has been extensively studied, the function of DNA remains elusive. Here, we distinguished novel heterogeneous subpopulations of small extracellular vesicles (sEVs) based on their DNA content and topology. Low- and high-density sEV subsets from a human mast cell line (HMC-1) and an erythroleukemic cell line (TF-1) were separated using high-resolution iodixanol density gradients to discriminate the nature of the DNA cargo of the sEVs. Paired comparisons of the sEV-associated DNA and RNA molecules showed that RNA was more abundant than DNA and that most of the DNA was present in the high-density fractions, demonstrating that sEV subpopulations have different DNA content. DNA was predominately localised on the outside or surface of sEVs, with only a small portion being protected from enzymatic degradation. Whole-genome sequencing identified DNA fragments spanning all chromosomes and mitochondrial DNA when sEVs were analysed in bulk. Our work contributes to the understanding of how DNA is associated with sEVs and thus provides direction for distinguishing subtypes of EVs based on their DNA cargo and topology.
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| 15. |
- Lunavat, Taral R, et al.
(författare)
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RNAi delivery by exosome-mimetic nanovesicles - Implications for targeting c-Myc in cancer
- 2016
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Ingår i: Biomaterials. - : Elsevier BV. - 0142-9612. ; 102, s. 231-238
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Tidskriftsartikel (refereegranskat)abstract
- To develop RNA-based therapeutics, it is crucial to create delivery vectors that transport the RNA molecule into the cell cytoplasm. Naturally released exosomes vesicles (also called "Extracellular Vesicles") have been proposed as possible RNAi carriers, but their yield is relatively small in any cell culture system. We have previously generated exosome-mimetic nanovesicles (NV) by serial extrusions of cells through nano-sized filters, which results in 100-times higher yield of extracellular vesicles. We here test 1) whether NV can be loaded with siRNA exogenously and endogenously, 2) whether the siRNA-loaded NV are taken up by recipient cells, and 3) whether the siRNA can induce functional knock-down responses in recipient cells. A siRNA against GFP was first loaded into NV by electroporation, or a c-Myc shRNA was expressed inside of the cells. The NV were efficiently loaded with siRNA with both techniques, were taken up by recipient cells, which resulted in attenuation of target gene expression. In conclusion, our study suggests that exosome-mimetic nanovesicles can be a platform for RNAi delivery to cell cytoplasm.
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| 16. |
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| 17. |
- Lässer, Cecilia, 1981, et al.
(författare)
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Subpopulations of extracellular vesicles and their therapeutic potential
- 2018
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Ingår i: Molecular Aspects of Medicine. - : Elsevier BV. - 0098-2997. ; 60, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs), such as exosomes and microvesicles, have over the last 10-15 years been recognized to convey key messages in the molecular communication between cells. Indeed, EVs have the capacity to shuttle proteins, lipids, and nucleotides such as RNA between cells, leading to an array of functional changes in the recipient cells. Importantly, the EV secretome changes significantly in diseased cells and under conditions of cellular stress. More recently, it has become evident that the EV secretome is exceptionally diverse, with many different types of EVs being released by a single cell type, and these EVs can be described in terms of differences in density, molecular cargos, and morphology. This review will discuss the diversity of EVs, will introduce some suggestions for how to categorize them, and will propose how EVs and their subpopulations might be used for very different therapeutic purposes.
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| 18. |
- Shelke, Ganesh V, 1986, et al.
(författare)
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Endosomal signalling via exosome surface TGF beta-1
- 2019
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Ingår i: Journal of Extracellular Vesicles. - : Wiley. - 2001-3078. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles such as exosomes convey biological messages between cells, either by surface-to-surface interaction or by shuttling of bioactive molecules to a recipient cell's cytoplasm. Here we show that exosomes released by mast cells harbour both active and latent transforming growth factor beta-1 (TGF beta-1) on their surfaces. The latent form of TGF beta-1 is associated with the exosomes via heparinase-II and pH-sensitive elements. These vesicles traffic to the endocytic compartment of recipient human mesenchymal stem cells (MSCs) within 60 min of exposure. Further, the exosomes-associated TGF beta-1 is retained within the endosomal compartments at the time of signalling, which results in prolonged cellular signalling compared to free-TGF beta-1. These exosomes induce a migratory phenotype in primary MSCs involving SMAD-dependent pathways. Our results show that mast cell-derived exosomes are decorated with latent TGF beta-1 and are retained in recipient MSC endosomes, influencing recipient cell migratory phenotype. We conclude that exosomes can convey signalling within endosomes by delivering bioactive surface ligands to this intracellular compartment.
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| 19. |
- Tüzesi, Ágota, 1982, et al.
(författare)
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Pediatric brain tumor cells release exosomes with a miRNA repertoire that differs from exosomes secreted by normal cells
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:52, s. 90164-90175
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Tidskriftsartikel (refereegranskat)abstract
- High-grade gliomas (HGGs) are very aggressive brain tumors with a cancer stem cell component. Cells, including cancer stem cells, release vesicles called exosomes which contain small non-coding RNAs such as microRNAs (miRNAs). These are thought to play an important role in cell-cell communication. However, we have limited knowledge of the types of exosomal miRNAs released by pediatric HGG stem cells; a prerequisite for exploring their potential roles in HGG biology. Here we isolated exosomes released by pediatric glioma stem cells (GSCs) and compared their repertoire of miRNAs to genetically normal neural stem cells (NSCs) exosomes, as well as their respective cellular miRNA content. Whereas cellular miRNAs are similar, we find that the exosomal miRNA profiles differ between normal and tumor cells, and identify several differentially expressed miRNAs. Of particular interest is miR-1290 and miR-1246, which have previously been linked to 'stemness' and invasion in other cancers. We demonstrate that GSC-secreted exosomes influence the gene expression of receiving NSCs, particularly targeting genes with a role in cell fate and tumorigenesis. Thus, our study shows that GSCs and NSCs have similar cellular miRNA profiles, yet differ significantly in the repertoire of exosomal miRNAs and these could influence malignant features of HGG. © Tuzesi et al.
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