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Search terms: exosomes OR "extracellular vesicles" OR microvesicles OR microparticles. Direct link to the PubMed search here.

Increased expression of miR142 and miR155 in glial and immune cells after traumatic brain injury may contribute to neuroinflammation via astrocyte activation.

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Increased expression of miR142 and miR155 in glial and immune cells after traumatic brain injury may contribute to neuroinflammation via astrocyte activation.

Brain Pathol. 2020 May 27;:

Authors: Korotkov A, Puhakka N, Gupta SD, Vuokila N, Broekaart DWM, Anink JJ, Heiskanen M, Karttunen J, van Scheppingen J, Huitinga I, Mills JD, van Vliet EA, Pitkänen A, Aronica E

Abstract
Traumatic brain injury (TBI) is associated with the pathological activation of immune-competent cells in the brain, such as astrocytes, microglia, and infiltrating immune blood cells, resulting in chronic inflammation and gliosis. This may contribute to the secondary injury after TBI, thus understanding of these processes is crucial for the development of effective treatments of post-traumatic pathologies. MicroRNAs (miRNAs, miRs) are small non-coding RNAs, functioning as post-transcriptional regulators of gene expression. The increased expression of inflammation-associated microRNAs miR155 and miR142 has been reported after TBI in rats. However, expression of these miRNAs in the human brain post-TBI is not studied and their functions are not well understood. Moreover, circulating miR155 and miR142 are candidate biomarkers. Therefore, we characterized miR142 and miR155 expression in the perilesional cortex and plasma of rats that underwent lateral fluid-percussion injury, a model for TBI, and in the human perilesional cortex post-TBI. We demonstrated higher miR155 and miR142 expression in the perilesional cortex of rats 2 weeks post-TBI. In plasma, miR155 was associated with proteins and miR142 with extracellular vesicles, however their expression did not change. In the human perilesional cortex miR155 was most prominently expressed by activated astrocytes, whereas miR142 was expressed predominantly by microglia, macrophages and lymphocytes. Pro-inflammatory medium from macrophage-like cells stimulated miR155 expression in astrocytes and overexpression of miR142 in these cells further potentiated a pro-inflammatory state of activated astrocytes. We conclude that miR155 and miR142 promote brain inflammation via astrocyte activation and may be involved in the secondary brain injury after TBI.

PMID: 32460356 [PubMed - as supplied by publisher]

Mentalexo approach for diagnosis of psychiatric disorders.

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Mentalexo approach for diagnosis of psychiatric disorders.

Med Hypotheses. 2020 May 12;143:109823

Authors: Topuzoğlu A, Ilgın C

Abstract
INTRODUCTION: Psychiatric disorders cause a high burden of disease and disability for the society. Liquid biopsies provide potent opportunities for screening programs, diagnosis, prognostic stratification and treatment monitorization. Previously, the liquid biopsy studies were mainly focused on the several malignancies without proper screen methods, but this approach has also a strong potential for decreasing disease burden in CNS pathologies. The main restriction for the diagnosis of CNS diseases is the lack of the methods to receive biochemical/functional information form a tightly enveloped compartment.
THE HYPOTHESIS/THEORY: In this proposal, we aim to develop a fast and cheap diagnostic platform based on the detection of exosomes originating from the central nervous system (CNS) cells. We intended to develop a sensor device with minimum maintenance costs, which is highly specific and sensitive for psychiatric diseases.
EVALUATION OF THE HYPOTHESIS/IDEA: In order to give background information for our proposal; we began with reviewing the concept of liquid biopsies and adaptation of this concept for psychiatric disorders. Then we discussed the conventional and novel methods for the detection of extracellular vesicles (EV). Furthermore, we discussed the detection of exosomes originating from central nervous system and methods analyzing the content of the EVs. Additionally, we reviewed the imaging techniques for detection and visualization of EVs.
EMPIRICAL DATA: We used in silico research tools (MetaCore™ version 6.37, Clarivate Analytics, and ExoCarta database) to detect appropriate disease specific exosomal markers. We proposed our design for the detection of EVs based on the immune-capture of EVs and detection of surface antigens via the antibody conjugated fluorophores. We also proposed a design to increase the channels for detection of exosomal antigens by using bioinformatics methods, including pathway networks, RDOC matrices and exosome databases which we called "Mentalexo" approach. We applied this approach on depression and addiction disorders in order to find appropriate exosomal markers.
CONSEQUENCES OF THE HYPOTHESIS AND DISCUSSION: We believe that our proposal may contribute to the conception of new diagnostic devices focusing on the detection of exosomes in psychiatric conditions.

PMID: 32460206 [PubMed - as supplied by publisher]

Immune Cell-Derived Exosomes in the Cancer-Immunity Cycle.

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Immune Cell-Derived Exosomes in the Cancer-Immunity Cycle.

Trends Cancer. 2020 Jun;6(6):506-517

Authors: Yan W, Jiang S

Abstract
Cells can communicate through extracellular vesicle (EV) secretion and uptake. Exosomes are lipid bilayer-enclosed EVs of 30-150 nm in diameter, which can transfer RNA, functional proteins, lipids, and metabolites to recipient cells in vivo. Most cell types, including immune cells, can secrete and uptake exosomes. Biogenesis, secretion, and uptake of immune cell-derived exosomes are regulated by intracellular proteins and extracellular stimuli. Immune cell-derived exosomes can mediate crosstalk between innate and adaptive immunity and regulate cancer progression and metastasis. The dichotomous roles of immune cell-derived exosomes towards tumor cells can induce suppressive or active immune responses. Hence, immune cell-secreted exosomes may have applications in cancer diagnosis and immunotherapy and could potentially be developed for vaccination and chemotherapy drug transportation.

PMID: 32460004 [PubMed - as supplied by publisher]

Improved Flow Cytometric Light Scatter Detection of Submicron-Sized Particles by Reduction of Optical Background Signals.

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Improved Flow Cytometric Light Scatter Detection of Submicron-Sized Particles by Reduction of Optical Background Signals.

Cytometry A. 2020 May 27;:

Authors: Arkesteijn GJA, Lozano-Andrés E, Libregts SFWM, Wauben MHM

Abstract
Flow cytometry allows multiparameter analysis on a single-cell basis and is currently the method of choice to rapidly assess heterogeneity of cell populations in suspension. With the research field of extracellular vesicles (EV) rapidly expanding, there is an increased demand to address heterogeneity of EV populations in biological samples. Although flow cytometry would be the ideal technique to do so, the available instruments are in general not equipped to optimally detect the dim light scatter signals generated by submicron-sized particles like EV. Although sideward scatter light and fluorescence are currently used as a threshold signal to identify EV within samples, the forward scatter light (FSC) parameter is often neglected due to the lack of resolution to distinguish EV-related signals from noise. However, after optimization of FSC detection by adjusting the size of the obscuration bar, we recently showed that certain EV-subsets could only be identified based on FSC. This observation made us to further study the possibilities to enhance FSC-detection of submicron-sized particles. By testing differently sized obscuration bars and differently sized pinholes in the focal plane behind the FSC detection lens, we generated a matrix that allowed us to determine which combination resulted in the lowest optical background in terms of numbers of events regarding FSC detection of submicron-sized particles. We found that a combination of an 8-mm obscuration bar and a 200-μm pinhole reduced optical background in a reproducible manner to such extent that it allowed a robust separation of 100-nm polystyrene beads from background signals within the FSC channel, and even allowed thresholding on FSC without the interference of massive background signals when both beads and EV were measured. These technical adaptations thus significantly improved FSC detection of submicron-sized particles and provide an important lead for the further development and design of flow cytometers that aid in detection of submicron-sized particles. © 2020 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

PMID: 32459071 [PubMed - as supplied by publisher]

A novel multi-marker discovery approach identifies new serum biomarkers for Parkinson's disease in older people: an EXosomes in PArkiNson Disease (EXPAND) ancillary study.

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A novel multi-marker discovery approach identifies new serum biomarkers for Parkinson's disease in older people: an EXosomes in PArkiNson Disease (EXPAND) ancillary study.

Geroscience. 2020 May 26;:

Authors: Calvani R, Picca A, Landi G, Marini F, Biancolillo A, Coelho-Junior HJ, Gervasoni J, Persichilli S, Primiano A, Arcidiacono A, Urbani A, Bossola M, Bentivoglio AR, Cesari M, Bernabei R, Monaco MRL, Marzetti E

Abstract
Dopaminergic nigrostriatal denervation and widespread intracellular α-synuclein accumulation are neuropathologic hallmarks of Parkinson's disease (PD). A constellation of peripheral processes, including metabolic and inflammatory changes, are thought to contribute to neurodegeneration. In the present study, we sought to obtain insight into the multifaceted pathophysiology of PD through the application of a multi-marker discovery approach. Fifty older adults aged 70+, 20 with PD and 30 age-matched controls were enrolled as part of the EXosomes in PArkiNson Disease (EXPAND) study. A panel of 68 circulating mediators of inflammation, neurogenesis and neural plasticity, and amino acid metabolism was assayed. Biomarker selection was accomplished through sequential and orthogonalized covariance selection (SO-CovSel), a multi-platform regression method developed to handle highly correlated variables organized in multi-block datasets. The SO-CovSel model with the best prediction ability using the smallest number of variables was built with seven biomolecules. The model allowed correct classification of 94.2 ± 3.1% participants with PD and 100% controls. The biomarker profile of older adults with PD was defined by higher circulating levels of interleukin (IL) 8, macrophage inflammatory protein (MIP)-1β, phosphoethanolamine, and proline, and by lower concentrations of citrulline, IL9, and MIP-1α. Our innovative approach allowed identifying and evaluating the classification performance of a set of potential biomarkers for PD in older adults. Future studies are warranted to establish whether these biomolecules could serve as biomarkers for PD as well as unveil new targets for interventions.

PMID: 32458283 [PubMed - as supplied by publisher]

Caveolin-1 function at the plasma membrane and in intracellular compartments in cancer.

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Caveolin-1 function at the plasma membrane and in intracellular compartments in cancer.

Cancer Metastasis Rev. 2020 May 27;:

Authors: Simón L, Campos A, Leyton L, Quest AFG

Abstract
Caveolin-1 (CAV1) is commonly considered to function as a cell surface protein, for instance in the genesis of caveolae. Nonetheless, it is also present in many intracellular organelles and compartments. The contributions of these intracellular pools to CAV1 function are generally less well understood, and this is also the case in the context of cancer. This review will summarize literature available on the role of CAV1 in cancer, highlighting particularly our understanding of the canonical (CAV1 in the plasma membrane) and non-canonical pathways (CAV1 in organelles and exosomes) linked to the dual role of the protein as a tumor suppressor and promoter of metastasis. With this in mind, we will focus on recently emerging concepts linking CAV1 function to the regulation of intracellular organelle communication within the same cell where CAV1 is expressed. However, we now know that CAV1 can be released from cells in exosomes and generate systemic effects. Thus, we will also elaborate on how CAV1 participates in intracellular communication between organelles as well as signaling between cells (non-canonical pathways) in cancer.

PMID: 32458269 [PubMed - as supplied by publisher]

Extracellular Vesicles in Renal Cell Carcinoma: Multifaceted Roles and Potential Applications Identified by Experimental and Computational Methods.

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Extracellular Vesicles in Renal Cell Carcinoma: Multifaceted Roles and Potential Applications Identified by Experimental and Computational Methods.

Front Oncol. 2020;10:724

Authors: Qin Z, Xu Q, Hu H, Yu L, Zeng S

Abstract
Renal cell carcinoma (RCC) is the most common type of kidney cancer. Increasingly evidences indicate that extracellular vesicles (EVs) orchestrate multiple processes in tumorigenesis, metastasis, immune evasion, and drug response of RCC. EVs are lipid membrane-bound vesicles in nanometer size and secreted by almost all cell types into the extracellular milieu. A myriad of bioactive molecules such as RNA, DNA, protein, and lipid are able to be delivered via EVs for the intercellular communication. Hence, the abundant content of EVs is appealing reservoir for biomarker identification through computational analysis and experimental validation. EVs with excellent biocompatibility and biodistribution are natural platforms that can be engineered to offer achievable drug delivery strategies for RCC therapies. Moreover, the multifaceted roles of EVs in RCC progression also provide substantial targets and facilitate EVs-based drug discovery, which will be accelerated by using artificial intelligence approaches. In this review, we summarized the vital roles of EVs in occurrence, metastasis, immune evasion, and drug resistance of RCC. Furthermore, we also recapitulated and prospected the EVs-based potential applications in RCC, including biomarker identification, drug vehicle development as well as drug target discovery.

PMID: 32457844 [PubMed]

Novel Role of Endothelial Derived Exosomal HSPA12B in Regulating Macrophage Inflammatory Responses in Polymicrobial Sepsis.

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Novel Role of Endothelial Derived Exosomal HSPA12B in Regulating Macrophage Inflammatory Responses in Polymicrobial Sepsis.

Front Immunol. 2020;11:825

Authors: Tu F, Wang X, Zhang X, Ha T, Wang Y, Fan M, Yang K, Gill PS, Ozment TR, Dai Y, Liu L, Williams DL, Li C

Abstract
Endothelial cell dysfunction contributes to sepsis induced initiate immune response and the infiltration of immune cells into organs, resulting in organ injury. Heat shock protein A12B (HSPA12B) is predominantly expressed in endothelial cells. The present study investigated whether endothelial HSPA12B could regulate macrophage pro-inflammatory response during sepsis. Wild type (WT) and endothelial cell-specific HSPA12B deficient (HSPA12B-/-) mice were subjected to CLP sepsis. Mortality and cardiac function were monitored. Higher mortality, worsened cardiac dysfunction, and greater infiltrated macrophages in the myocardium and spleen were observed in HSPA12B-/- septic mice compared with the WT septic mice. The serum levels of TNF-α and IL-1β were higher and the levels of IL-10 were lower in HSPA12B-/- septic mice than in WT septic mice. Importantly, endothelial exosomes contain HSPA12B which can be uptaken by macrophages. Interestingly, endothelial exosomal HSPA12B significantly increases IL-10 levels and decreases TNF-α and IL-1β production in LPS-stimulated macrophages. Mechanistic studies show that endothelial exosomal HSPA12B downregulates NF-κB activation and nuclear translocation in LPS stimulated macrophages. These data suggest that endothelial HSPA12B plays a novel role in the regulation of macrophage pro-inflammatory response via exosomes during sepsis and that sepsis induced cardiomyopathy and mortality are associated with endothelial cell deficiency of HSPA12B.

PMID: 32457753 [PubMed - in process]

RNA delivery by extracellular vesicles in mammalian cells and its applications.

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RNA delivery by extracellular vesicles in mammalian cells and its applications.

Nat Rev Mol Cell Biol. 2020 May 26;:

Authors: O'Brien K, Breyne K, Ughetto S, Laurent LC, Breakefield XO

Abstract
The term 'extracellular vesicles' refers to a heterogeneous population of vesicular bodies of cellular origin that derive either from the endosomal compartment (exosomes) or as a result of shedding from the plasma membrane (microvesicles, oncosomes and apoptotic bodies). Extracellular vesicles carry a variety of cargo, including RNAs, proteins, lipids and DNA, which can be taken up by other cells, both in the direct vicinity of the source cell and at distant sites in the body via biofluids, and elicit a variety of phenotypic responses. Owing to their unique biology and roles in cell-cell communication, extracellular vesicles have attracted strong interest, which is further enhanced by their potential clinical utility. Because extracellular vesicles derive their cargo from the contents of the cells that produce them, they are attractive sources of biomarkers for a variety of diseases. Furthermore, studies demonstrating phenotypic effects of specific extracellular vesicle-associated cargo on target cells have stoked interest in extracellular vesicles as therapeutic vehicles. There is particularly strong evidence that the RNA cargo of extracellular vesicles can alter recipient cell gene expression and function. During the past decade, extracellular vesicles and their RNA cargo have become better defined, but many aspects of extracellular vesicle biology remain to be elucidated. These include selective cargo loading resulting in substantial differences between the composition of extracellular vesicles and source cells; heterogeneity in extracellular vesicle size and composition; and undefined mechanisms for the uptake of extracellular vesicles into recipient cells and the fates of their cargo. Further progress in unravelling the basic mechanisms of extracellular vesicle biogenesis, transport, and cargo delivery and function is needed for successful clinical implementation. This Review focuses on the current state of knowledge pertaining to packaging, transport and function of RNAs in extracellular vesicles and outlines the progress made thus far towards their clinical applications.

PMID: 32457507 [PubMed - as supplied by publisher]

Ovarian Cancer Exosomes Trigger Differential Biophysical Response in Tumor-Derived Fibroblasts.

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Ovarian Cancer Exosomes Trigger Differential Biophysical Response in Tumor-Derived Fibroblasts.

Sci Rep. 2020 May 26;10(1):8686

Authors: Lee AH, Ghosh D, Quach N, Schroeder D, Dawson MR

Abstract
Exosomes are cell-secreted microvesicles that play important roles in epithelial ovarian cancer (EOC) progression, as they are constantly secreted into ascites fluids. While cells spontaneously release exosomes, alterations in intracellular calcium or extracellular pH can release additional exosomes. Yet, little is known about how these exosomes compare to those that are continuously released without stimulation and how they mediate cellular activities important in cancer progression. Here, we demonstrate that chelation of extracellular calcium leads to release of chelation-induced exosomes (CI-exosomes) from OVCAR-3 EOC cells. CI-exosomes display a unique miRNA profile compared to naturally secreted exosomes (SEC-exosomes). Furthermore, treatment with CI- and SEC-exosomes leads to differential biophysical and functional changes including, adhesion and migration in EOC-derived fibroblasts that suggest the development of a malignant tumor microenvironment. This result highlights how tumor environmental factors contribute to heterogeneity in exosome populations and how different exosome populations mediate diversity in stromal cell behavior.

PMID: 32457479 [PubMed - in process]

Bovine Milk Exosomes Affect Proliferation and Protect Macrophages against Cisplatin-Induced Cytotoxicity.

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Bovine Milk Exosomes Affect Proliferation and Protect Macrophages against Cisplatin-Induced Cytotoxicity.

Immunol Invest. 2020 May 27;:1-15

Authors: Matic S, D'Souza DH, Wu T, Pangloli P, Dia VP

Abstract
BACKGROUND: Exosomes are extracellular vesicles involved in intercellular communication. The objectives were to characterize bovine milk exosomes (BME) and determine its effect on RAW 264.7 macrophages.
METHODS: BME were isolated using differential centrifugation and characterized by particle size and the presence of exosomal markers Alix, TSG101, and CD81. The effect of in vitro digestion and different pH on the stability of BME was investigated. The biological activity of BME in RAW 264.7 macrophages was conducted by assessing proliferation and cell cycle. Moreover, the protective effect of exosomes on cisplatin-induced cytotoxicity was evaluated.
RESULTS: BME have an average particle size of 106.8 ± 3.4 nm and expressed Alix, TSG101, and CD81. TSG101 was detected after digestion and exposure to different pH values. Cell-cycle analysis showed that BME reduced the percentage of apoptotic cells while arresting the cells in G2/M phase accompanied by differential expression of proliferation markers p53, p21, cyclin D1, and β-catenin. Exosomes protected macrophages against cisplatin-induced cytotoxicity.
CONCLUSION: Our results showed for the first time the effect of BME on the proliferation of RAW 264.7 macrophages and its protective effect against chemotherapeutic drug-induced cytotoxicity. Potential effect of BME on immune system must be studied.

PMID: 32456495 [PubMed - as supplied by publisher]

Joint Reconstituted Signaling of the IL-6 Receptor via Extracellular Vesicles.

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Joint Reconstituted Signaling of the IL-6 Receptor via Extracellular Vesicles.

Cells. 2020 May 24;9(5):

Authors: Arnold P, Lückstädt W, Li W, Boll I, Lokau J, Garbers C, Lucius R, Rose-John S, Becker-Pauly C

Abstract
Interleukin-6 (IL-6) signaling is a crucial regulatory event important for many biological functions, such as inflammation and tissue regeneration. Accordingly, several pathological conditions are associated with dysregulated IL-6 activity, making it an attractive therapeutic target. For instance, blockade of IL-6 or its α-receptor (IL-6R) by monoclonal antibodies has been successfully used to treat rheumatoid arthritis. However, based on different signaling modes, IL-6 function varies between pro- and anti-inflammatory activity, which is critical for therapeutic intervention. So far, three modes of IL-6 signaling have been described, the classic anti-inflammatory signaling, as well as pro-inflammatory trans-signaling, and trans-presentation. The IL-6/IL-6R complex requires an additional β-receptor (gp130), which is expressed on almost all cells of the human body, to induce STAT3 (signal transducer and activator of signal transcription 3) phosphorylation and subsequent transcriptional regulation. In contrast, the IL-6R is expressed on a limited number of cells, including hepatocytes and immune cells. However, the proteolytic release of the IL-6R enables trans-signaling on cells expressing gp130 only. Here, we demonstrate a fourth possibility of IL-6 signaling that we termed joint reconstituted signaling (JRS). We show that IL-6R on extracellular vesicles (EVs) can also be transported to and fused with other cells that lack the IL-6R on their surface. Importantly, JRS via EVs induces delayed STAT3 phosphorylation compared to the well-established trans-signaling mode. EVs isolated from human serum were already shown to carry the IL-6R, and thus this new signaling mode should be considered with regard to signal intervention.

PMID: 32456348 [PubMed - in process]

Injectable SN-38-embedded Polymeric Microparticles Promote Antitumor Efficacy against Malignant Glioma in an Animal Model.

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Injectable SN-38-embedded Polymeric Microparticles Promote Antitumor Efficacy against Malignant Glioma in an Animal Model.

Pharmaceutics. 2020 May 24;12(5):

Authors: Tseng YY, Yang TC, Chen SM, Yang ST, Tang YL, Liu SJ

Abstract
Malignant glioma (MG) is extremely aggressive and highly resistant to chemotherapeutic agents. Using electrospraying, the potent chemotherapeutic agent 7-ethyl-10-hydroxycamptothecia (SN-38) was embedded into 50:50 biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA) microparticles (SMPs). The SMPs were stereotactically injected into the brain parenchyma of healthy rats and intratumorally injected into F98 glioma-bearing rats for estimating the pharmacodynamics and therapeutic efficacy. SN-38 was rapidly released after injection and its local (brain tissue) concentration remained much higher than that in the blood for more than 8 weeks. Glioma-bearing rats were divided into three groups-group A (n = 13; stereotactically injected pure PLGA microparticles), group B (n = 12; stereotactically injected Gliadel wafer and oral temozolomide), and group C (n = 13; stereotactic and intratumoral introduction of SMPs). The SMPs exhibited significant therapeutic efficacy, with prolonged survival, retarded tumor growth, and attenuated malignancy. The experimental results demonstrated that SMPs provide an effective and potential strategy for the treatment of MG.

PMID: 32456305 [PubMed]

Lung Tumor Cell-Derived Exosomes Promote M2 Macrophage Polarization.

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Lung Tumor Cell-Derived Exosomes Promote M2 Macrophage Polarization.

Cells. 2020 May 24;9(5):

Authors: Pritchard A, Tousif S, Wang Y, Hough K, Khan S, Strenkowski J, Chacko BK, Darley-Usmar VM, Deshane JS

Abstract
Cellular cross-talk within the tumor microenvironment (TME) by exosomes is known to promote tumor progression. Tumor promoting macrophages with an M2 phenotype are suppressors of anti-tumor immunity. However, the impact of tumor-derived exosomes in modulating macrophage polarization in the lung TME is largely unknown. Herein, we investigated if lung tumor-derived exosomes alter transcriptional and bioenergetic signatures of M0 macrophages and polarize them to an M2 phenotype. The concentration of exosomes produced by p53 null H358 lung tumor cells was significantly reduced compared to A549 (p53 wild-type) lung tumor cells, consistent with p53-mediated regulation of exosome production. In co-culture studies, M0 macrophages internalized tumor-derived exosomes, and differentiated into M2 phenotype. Importantly, we demonstrate that tumor-derived exosomes enhance the oxygen consumption rate of macrophages, altering their bioenergetic state consistent with that of M2 macrophages. In vitro co-cultures of M0 macrophages with H358 exosomes demonstrated that exosome-induced M2 polarization may be p53 independent. Murine bone marrow cells and bone marrow-derived myeloid-derived suppressor cells (MDSCs) co-cultured with lewis lung carcinoma (LLC)-derived exosomes differentiated to M2 macrophages. Collectively, these studies provide evidence for a novel role for lung tumor-exosomes in M2 macrophage polarization, which then offers new therapeutic targets for immunotherapy of lung cancer.

PMID: 32456301 [PubMed - in process]

N-Terminal Fatty Acids of NEFMUT Are Required for the CD8+ T-Cell Immunogenicity of In Vivo Engineered Extracellular Vesicles.

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N-Terminal Fatty Acids of NEFMUT Are Required for the CD8+ T-Cell Immunogenicity of In Vivo Engineered Extracellular Vesicles.

Vaccines (Basel). 2020 May 22;8(2):

Authors: Chiozzini C, Manfredi F, Arenaccio C, Ferrantelli F, Leone P, Federico M

Abstract
We recently described a cytotoxic CD8+ T lymphocyte (CTL) vaccine platform based on the intramuscular (i.m.) injection of DNA eukaryotic vectors expressing antigens of interest fused at the C-terminus of HIV-1 Nefmut, i.e., a functionally defective mutant that is incorporated at quite high levels into exosomes/extracellular vesicles (EVs). This system has been proven to elicit strong CTL immunity against a plethora of both viral and tumor antigens, as well as inhibit both transplantable and orthotopic tumors in mice. However, a number of open issues remain regarding the underlying mechanism. Here we provide evidence that hindering the uploading into EVs of Nefmut-derived products by removing the Nefmut N-terminal fatty acids leads to a dramatic reduction of the downstream antigen-specific CD8+ T-cell activation after i.m. injection of DNA vectors in mice. This result formally demonstrates that the generation of engineered EVs is part of the mechanism underlying the in vivo induced CD8+ T-cell immunogenicity. Gaining new insights on the EV-based vaccine platform can be relevant in view of its possible translation into the clinic to counteract both chronic and acute infections as well as tumors.

PMID: 32456079 [PubMed]

The Role of Tumor-Associated Macrophages in the Progression and Chemoresistance of Ovarian Cancer.

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The Role of Tumor-Associated Macrophages in the Progression and Chemoresistance of Ovarian Cancer.

Cells. 2020 May 22;9(5):

Authors: Nowak M, Klink M

Abstract
Tumor-associated macrophages (TAMs) constitute the main population of immune cells present in the ovarian tumor microenvironment. These cells are characterized by high plasticity and can be easily polarized by colony-stimulating factor-1, which is released by tumor cells, into an immunosuppressive M2-like phenotype. These cells are strongly implicated in both the progression and chemoresistance of ovarian cancer. The main pro-tumoral function of M2-like TAMs is the secretion of a variety of cytokines, chemokines, enzymes and exosomes that reach microRNAs, directly inducing the invasion potential and chemoresistance of ovarian cancer cells by triggering their pro-survival signaling pathways. The M2-like TAMs are also important players in the metastasis of ovarian cancer cells in the peritoneum through their assistance in spheroid formation and attachment of cancer cells to the metastatic area-the omentum. Moreover, TAMs interplay with other immune cells, such as lymphocytes, natural killer cells, and dendritic cells, to inhibit their responsiveness, resulting in the development of immunosuppression. The detrimental character of the M2-like type of TAMs in ovarian tumors has been confirmed by a number of studies, demonstrating the positive correlation between their high level in tumors and low overall survival of patients.

PMID: 32456078 [PubMed - in process]

Therapeutic Use of Mesenchymal Stem Cell-Derived Exosomes: From Basic Science to Clinics.

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Therapeutic Use of Mesenchymal Stem Cell-Derived Exosomes: From Basic Science to Clinics.

Pharmaceutics. 2020 May 22;12(5):

Authors: Harrell CR, Jovicic N, Djonov V, Volarevic V

Abstract
Mesenchymal stem cells (MSC) are, due to their immunosuppressive and regenerative properties, used as new therapeutic agents in cell-based therapy of inflammatory and degenerative diseases. A large number of experimental and clinical studies revealed that most of MSC-mediated beneficial effects were attributed to the effects of MSC-sourced exosomes (MSC-Exos). MSC-Exos are nano-sized extracellular vesicles that contain MSC-derived bioactive molecules (messenger RNA (mRNA), microRNAs (miRNAs)), enzymes, cytokines, chemokines, and growth factors) that modulate phenotype, function and homing of immune cells, and regulate survival and proliferation of parenchymal cells. In this review article, we emphasized current knowledge about molecular and cellular mechanisms that were responsible for MSC-Exos-based beneficial effects in experimental models and clinical trials. Additionally, we elaborated on the challenges of conventional MSC-Exos administration and proposed the use of new bioengineering and cellular modification techniques which could enhance therapeutic effects of MSC-Exos in alleviation of inflammatory and degenerative diseases.

PMID: 32456070 [PubMed]

The Role of Extracellular Vesicles as Allies of HIV, HCV and SARS Viruses.

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The Role of Extracellular Vesicles as Allies of HIV, HCV and SARS Viruses.

Viruses. 2020 May 22;12(5):

Authors: Giannessi F, Aiello A, Franchi F, Percario ZA, Affabris E

Abstract
Extracellular vesicles (EVs) are lipid bilayer-enclosed entities containing proteins and nucleic acids that mediate intercellular communication, in both physiological and pathological conditions. EVs resemble enveloped viruses in both structural and functional aspects. In full analogy with viral biogenesis, some of these vesicles are generated inside cells and, once released into the extracellular milieu, are called "exosomes". Others bud from the plasma membrane and are generally referred to as "microvesicles". In this review, we will discuss the state of the art of the current studies on the relationship between EVs and viruses and their involvement in three important viral infections caused by HIV, HCV and Severe Acute Respiratory Syndrome (SARS) viruses. HIV and HCV are two well-known pathogens that hijack EVs content and release to create a suitable environment for viral infection. SARS viruses are a new entry in the world of EVs studies, but are equally important in this historical framework. A thorough knowledge of the involvement of the EVs in viral infections could be helpful for the development of new therapeutic strategies to counteract different pathogens.

PMID: 32456011 [PubMed - in process]

When Less Is More: Specific Capture and Analysis of Tumor Exosomes in Plasma Increases the Sensitivity of Liquid Biopsy for Comprehensive Detection of Multiple Androgen Receptor Phenotypes in Advanced Prostate Cancer Patients.

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When Less Is More: Specific Capture and Analysis of Tumor Exosomes in Plasma Increases the Sensitivity of Liquid Biopsy for Comprehensive Detection of Multiple Androgen Receptor Phenotypes in Advanced Prostate Cancer Patients.

Biomedicines. 2020 May 22;8(5):

Authors: Foroni C, Zarovni N, Bianciardi L, Bernardi S, Triggiani L, Zocco D, Venturella M, Chiesi A, Valcamonico F, Berruti A

Abstract
We evaluated the advantages and the reliability of novel protocols for the enrichment of tumor extracellular vesicles (EVs), enabling a blood-based test for the noninvasive parallel profiling of multiple androgen receptor (AR) gene alterations. Three clinically relevant AR variants related to response/resistance to standard-of-care treatments (AR-V7 transcript, AR T878A point mutation and AR gene amplification) were evaluated by digital PCR in 15 samples from patients affected by Castration-Resistant Prostate Cancer (CRPC). Plasma was processed to obtain circulating RNA and DNA using protocols based on tumor EVs enrichment through immuno-affinity and peptide-affinity compared to generic extraction kits. Our results showed that immuno-affinity enrichment prior to RNA extraction clearly outperforms the generic isolation method in the detection of AR-V7, also allowing for a distinction between responder (R) and non-responder (NR) patients. The T878A mutation was detected, overall, in nine out of 15 samples and no approach alone was able to reveal mutations in all harboring samples, showing that the employed methods complement each other. AR amplification was detected in the majority of CRPC samples analysed using either cell-free DNA (cfDNA) or exosome isolation kits (80%). We demonstrated that selective isolation of a subset of circulating exosomes enriched for tumor origin, rather than analysis of total plasma exosomes, or total plasma nucleic acids, increases sensitivity and specificity for the detection of specific alterations.

PMID: 32455948 [PubMed]

ASC-Exosomes Ameliorate the Disease Progression in SOD1(G93A) Murine Model Underlining Their Potential Therapeutic Use in Human ALS.

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ASC-Exosomes Ameliorate the Disease Progression in SOD1(G93A) Murine Model Underlining Their Potential Therapeutic Use in Human ALS.

Int J Mol Sci. 2020 May 21;21(10):

Authors: Bonafede R, Turano E, Scambi I, Busato A, Bontempi P, Virla F, Schiaffino L, Marzola P, Bonetti B, Mariotti R

Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motoneurons. To date, there is no effective treatment available. Exosomes are extracellular vesicles that play important roles in intercellular communication, recapitulating the effect of origin cells. In this study, we tested the potential neuroprotective effect of exosomes isolated from adipose-derived stem cells (ASC-exosomes) on the in vivo model most widely used to study ALS, the human SOD1 gene with a G93A mutation (SOD1(G93A)) mouse. Moreover, we compared the effect of two different routes of exosomes administration, intravenous and intranasal. The effect of exosomes administration on disease progression was monitored by motor tests and analysis of lumbar motoneurons and glial cells, neuromuscular junction, and muscle. Our results demonstrated that repeated administration of ASC-exosomes improved the motor performance; protected lumbar motoneurons, the neuromuscular junction, and muscle; and decreased the glial cells activation in treated SOD1(G93A) mice. Moreover, exosomes have the ability to home to lesioned ALS regions of the animal brain. These data contribute by providing additional knowledge for the promising use of ASC-exosomes as a therapy in human ALS.

PMID: 32455791 [PubMed - in process]

Metagenomic Analysis of Serum Microbe-Derived Extracellular Vesicles and Diagnostic Models to Differentiate Ovarian Cancer and Benign Ovarian Tumor.

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Metagenomic Analysis of Serum Microbe-Derived Extracellular Vesicles and Diagnostic Models to Differentiate Ovarian Cancer and Benign Ovarian Tumor.

Cancers (Basel). 2020 May 21;12(5):

Authors: Kim SI, Kang N, Leem S, Yang J, Jo H, Lee M, Kim HS, Dhanasekaran DN, Kim YK, Park T, Song YS

Abstract
We aimed to develop a diagnostic model identifying ovarian cancer (OC) from benign ovarian tumors using metagenomic data from serum microbe-derived extracellular vesicles (EVs). We obtained serum samples from 166 patients with pathologically confirmed OC and 76 patients with benign ovarian tumors. For model construction and validation, samples were randomly divided into training and test sets in the ratio 2:1. Isolation of microbial EVs from serum samples of the patients and 16S rDNA amplicon sequencing were carried out. Metagenomic and clinicopathologic data-based OC diagnostic models were constructed in the training set and then validated in the test set. There were significant differences in the metagenomic profiles between the OC and benign ovarian tumor groups; specifically, genus Acinetobacter was significantly more abundant in the OC group. More importantly, Acinetobacter was the only common genus identified by seven different statistical analysis methods. Among the various metagenomic and clinicopathologic data-based OC diagnostic models, the model consisting of age, serum CA-125 levels, and relative abundance of Acinetobacter showed the best diagnostic performance with the area under the receiver operating characteristic curve of 0.898 and 0.846 in the training and test sets, respectively. Thus, our findings establish a metagenomic analysis of serum microbe-derived EVs as a potential tool for the diagnosis of OC.

PMID: 32455705 [PubMed]

ASO Author Reflections: The Prognostic Role of Exosomal PD-L1 in Patients with Gastric Cancer.

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ASO Author Reflections: The Prognostic Role of Exosomal PD-L1 in Patients with Gastric Cancer.

Ann Surg Oncol. 2019 Dec;26(Suppl 3):851-852

Authors: Fan Y, Liu Y, Qu X

PMID: 31741108 [PubMed - indexed for MEDLINE]

 

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