Suchergebnisse

Imaging of the lymphatic vasculature has gained great attention in various fields, not only because lymphatic vessels act as a key draining system in the body, but also for their implication in autoimmune diseases, organ transplant, inflammation and cancer. Thus, neolymphangiogenesis, or the generation of new lymphatics, is typically an early event in the development of multiple tumor types, particularly in aggressive ones such as malignant melanoma. Still, the understanding of how lymphatic endothelial cells get activated at distal (pre)metastatic niches and their impact on therapy is still unclear. Addressing these questions is of particular interest in the case of immune modulators, because endothelial cells may favor or halt inflammatory processes depending on the cellular context. Therefore, there is great interest in visualizing the lymphatic vasculature in vivo. Here, we review imaging tools and mouse models used to analyze the lymphatic vasculature during tumor progression. We also discuss therapeutic approaches based on nanomedicines to target the lymphatic system and the potential use of extracellular vesicles to track and target sentinel lymph nodes. Finally, we summarize main pre-clinical models developed to visualize the lymphatic vasculature in vivo, discussing their applications with a particular focus in metastatic melanoma. ; The authors gratefully acknowledge the support of the following sources of funding: M.S.S. is funded by grants from the Spanish Ministry of Economy and Innovation (SAF2017-89533-R), Team Science and Established Investigator awards by the Melanoma Research Alliance, grants from Worldwide Cancer Research and Fundación 'La Caixa' Health Research 2019, and a collaborative grant from the Asociación Española Contra el Cáncer (AECC). H.P. acknowledges RETOS SAF2017-82924-R (AEI/10.13039/501100011033/FEDER-UE), Fundación Ramón Areces and La Caixa Foundation (HR-18-00256). We are also grateful for the support of the Translational NeTwork for the CLinical application of Extracellular VesicleS, TeNTaCLES. RED2018-102411-T(AEI/10.13039/501100011033). D.O. is funded by grants from the Spanish Ministry of Health (AES-PIS PI18/1057) and 'Fundación BBVA-Becas Leonardo a Investigadores y Creadores Culturales 2018'. D.C.-W. was a recipient of a predoctoral fellowship from Fundación 'La Caixa' and currently with a Cancer Research Institute Irvington Postdoctoral Fellowship. E.C. is funded by the European Union's Horizon 2020 research and innovation programme "proEVLifeCycle" under the Marie Skłodowska-Curie grant agreement No 860303. ; No

The UK Extracellular Vesicles (UKEV) Forum meetings were born of the realization that there were a number of UK laboratories studying extracellular vesicle biology and using similar techniques but without a regular national meeting dedicated to EVs at which to share their findings. This was compounded by the fact that many of these labs were working in different fields and thus networking and sharing of ideas and best practice was sometimes difficult. The first workshop was organized in 2013 by Dr Charlotte Lawson, under the auspices of the Society for Endocrinology, led to the founding of the UKEV Forum and the organization of a British Heart Foundation sponsored 1-day conference held in London in December 2014. Although growing in size every year, the central aims of these workshops have remained the same: to provide a forum for discussion and exchange of ideas, to allow young scientists to present their data in the form of short talks and poster presentations and to discuss their work with more established scientists in the field. Here we include the presented abstracts for the 2015 1-day conference hosted by Cardiff University. This meeting was attended by approximately 130 delegates throughout the United Kingdom, but also attended by delegates from Belgium, Netherlands, France, Ireland and other nations. The day composed of plenary presentations from Prof Matthias Belting, Lund University, Sweden and Dr Guillaume van Niel, Institut Curie, Paris together with 10 short presentations from submitted abstracts. The topics covered were broad, with sessions on Mechanisms of EV production, EVs in Infection, EVs in Cancer and in Blood and Characterizing EVs in Biological fluids. This hopefully gives a reflection of the range of EV-related studies being conducted currently in the UK. There were also 33 poster presentations equally broad in subject matter. The organizers are grateful to the Life Science Research Network Wales - a Welsh government-funding scheme that part-sponsored the conference. We are also grateful to commercial sponsors, and 3 paid-presentations are included in the abstracts. The UK EV Forum is expected to become an established annual event held at different Universities across the UK and continue to attract increasing delegate numbers and abstract submissions. We look forward to the next planned conference, which will be hosted by David Carter and his colleagues at Oxford Brookes University on 13th December 2016.

The recent discovery of microRNAs (miRNAs) in human reproductive tissues and cells indicates a possible functional role in reproductive function. However, the studies published to date in female reproductive tissues/cells and embryos are inconclusive and sometimes controversial. In order to update the knowledge of this field, the present study aimed to discuss, through a systematic review, the role of miRNAs in female human reproduction and early embryogenesis. We conducted a systematic review of the published literature in MEDLINE and EMBASE databases through June 2018 (plus a complementary search until July 2019), in accordance with the PRISMA guidelines. We have included descriptive and observational studies, in which fertile/infertile women were well-defined. The primary outcome was the miRNA expression in ovaries, oocytes, extracellular vesicles, and embryos. We identified 25,204 articles, of which 28 were selected for qualitative analysis: 18 in ovaries and extracellular vesicles, three in oocytes, and seven in embryos. The present systematic review of descriptive and observational studies demonstrates that aberrant miRNA expression in female reproductive tissues/cells and embryos is related with infertility and embryogenesis errors. The expression of specific miRNAs, particularly in extracellular vesicles, may be used in the future as biomarkers of infertility and prognostic tools of embryo development ; This research was funded by the Ministry of Science, Innovation and Universities, Spain (RYC-2014-15581), and the Regional Government of Catalonia, Spain (2017-SGR-1229)

Exosomes; Larynx cancer cells; Macrophages ; Exosomes; Cèl·lules cancerígenes de la laringe; Macròfags ; Exosomas; Células cancerosas de laringe; Macrófagos ; Background: Exosomes are cell-derived vesicles that mediate cellular communication in health and multiple diseases, including cancer. However, its role in head and neck cancer has been poorly defined. Here, we investigated the relevance of exosomes in the signaling between larynx cancer cells and macrophages. Methods: Exosomes from THP1 macrophages and BICR18 cells (a larynx squamous cell carcinoma cell line) were purified and their role in the cancer cell migration, macrophage phenotype and immunosuppressive activity was evaluated. The activation of STAT3 signal transduction in macrophages in response to exosomes obtained from cancer cells was also evaluated. Results: Macrophages foster the cancer cell migration and this effect is mediated by exosome signaling. On the other hand, exosomes also induce the expression of IL-10 in macrophages and PD-L1 in cancer cells, thus resulting in the promotion of an immunosuppressive environment. Moreover, we observed that the effects induced in cancer cells are mediated by the exosome-depending activation of STAT-3 signal transduction pathway. Conclusions: Our study indicates that exosomes released by both macrophages and cancer cells plays a critical role in tumor progression in larynx cancer and might be a potential target for therapeutic intervention in head and neck cancer. ; This work was supported by a research grant from the Carlos III Institute of Health with reference FIS PI16/00060 (D.C.), co-funded with European Union ERDF funds (European Regional Development Fund).

The prevention of neurodevelopmental disorders (NDD) of prenatal origin suffers from the lack of objective tools for early detection of susceptible individuals and the long time lag, usually in years, between the neurotoxic exposure and the diagnosis of mental dysfunction. Human data on the effects of alcohol, lead and mercury and experimental data from animals on developmental neurotoxins and their long term behavioral effects have achieved a critical mass, leading to the concept of the Developmental Origin of Health and Disease (DOHaD). However, there is currently no way to evaluate the degree of brain damage early after birth. We propose that Extracellular Vesicles (EVs) and particularly exosomes, released by brain cells into the fetal blood may offer us a non-invasive means of assessing brain damage by neurotoxins. We are inspired by the strategy applied by Alan Turing (a cryptanalyst working for the British government) who created a first computer to decrypt German intelligence communications during World War II. Given the growing evidence that miRNAs, which are among the molecules carried by EVs, are involved in cell-cell communication, we propose that decrypting messages from EVs can allow us to detect damage thus offering an opportunity to cure, reverse or prevent the development of NDD. This review summarizes recent findings on miRNAs associated with selected environmental toxicants known to be involved in the pathophysiology of NDD.

Background Exosomes are cell-derived vesicles that mediate cellular communication in health and multiple diseases, including cancer. However, its role in head and neck cancer has been poorly defined. Here, we investigated the relevance of exosomes in the signaling between larynx cancer cells and macrophages. Methods Exosomes from THP1 macrophages and BICR18 cells (a larynx squamous cell carcinoma cell line) were purified and their role in the cancer cell migration, macrophage phenotype and immunosuppressive activity was evaluated. The activation of STAT3 signal transduction in macrophages in response to exosomes obtained from cancer cells was also evaluated. Results Macrophages foster the cancer cell migration and this effect is mediated by exosome signaling. On the other hand, exosomes also induce the expression of IL-10 in macrophages and PD-L1 in cancer cells, thus resulting in the promotion of an immunosuppressive environment. Moreover, we observed that the effects induced in cancer cells are mediated by the exosome-depending activation of STAT-3 signal transduction pathway. Conclusions Our study indicates that exosomes released by both macrophages and cancer cells plays a critical role in tumor progression in larynx cancer and might be a potential target for therapeutic intervention in head and neck cancer. ; This work was supported by a research grant from the Carlos III Institute of Health with reference FIS PI16/00060 (D.C.), co-funded with European Union ERDF funds (European Regional Development Fund).

12 Pág. ; This research has been co-financed by the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH – CREATE – INNOVATE (Acronym: the summer cow, Project code: T1EDK-01078). Dimitrios Rizos was supported by the Spanish Ministry of Science and Innovation (PID2019-111641RB-I00), and Karina Cañon-Beltrán by Minciencias-Colombia Postdoctoral Fellowship (848–2019) ; Peer reviewed

AbstractPreeclampsia (PE) is a leading cause of maternal and fetal mortality and morbidity. While placental dysfunction is a core underlying issue, the pathogenesis of this disorder is thought to differ between early-onset (EOPE) and late-onset (LOPE) subtypes. As recent reports suggest that small extracellular vesicles (sEVs) contribute to the development of PE, we have compared systemic sEV concentrations between normotensive, EOPE, and LOPE pregnancies. To circumvent lengthy isolation techniques and intermediate filtration steps, a streamlined approach was developed to evaluate circulating plasma sEVs from maternal plasma. Polymer-based precipitation and purification were used to isolate total systemic circulating maternal sEVs, free from bias toward specific surface marker expression or extensive subpurification. Immediate Nanoparticle Tracking Analysis (NTA) of freshly isolated sEV samples afforded a comprehensive analysis that can be completed within hours, avoiding confounding freeze–thaw effects of particle aggregation and degradation.Rather than exosomal subpopulations, our findings indicate a significant elevation in the total number of circulating maternal sEVs in patients with EOPE. This streamlined approach also preserves sEV-bound protein and microRNA (miRNA) that can be used for potential biomarker analysis. This study is one of the first to demonstrate that maternal plasma sEVs harbor full-length hypoxia inducible factor 1 alpha (HIF-1α) protein, with EOPE sEVs carrying higher levels of HIF-1α compared to control sEVs. The detection of HIF-1α and its direct signaling partner microRNA-210 (miR-210) within systemic maternal sEVs lays the groundwork for identifying how sEV signaling contributes to the development of preeclampsia. When taken together, our quantitative and qualitative results provide compelling evidence to support the translational potential of streamlined sEV analysis for future use in the clinical management of patients with EOPE.

Extracellular vesicles (EVs) are small lipid vesicles released by either any prokaryotic or eukaryotic cell, or both, with a biological role in cell-to-cell communication. In this work, we characterize the proteomes and nanomechanical properties of EVs released by tissue-culture cell-derived trypomastigotes (mammalian infective stage; (TCT)) and epimastigotes (insect stage; (E)) of Trypanosoma cruzi, the etiologic agent of Chagas disease. EVs of each stage were isolated by differential centrifugation and analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS), dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), electron microscopy and atomic force microscopy (AFM). Measurements of zeta-potential were also included. Results show marked differences in the surface molecular cargos of EVs between both stages, with a noteworthy expansion of all groups of trans-sialidase proteins in trypomastigote's EVs. In contrast, chromosomal locations of trans-sialidases of EVs of epimastigotes were dramatically reduced and restricted to subtelomeric regions, indicating a possible regulatable expression of these proteins between both stages of the parasite. Regarding mechanical properties, EVs of trypomastigotes showed higher adhesion compared to the EVs of epimastigotes. These findings demonstrate the remarkable surface remodeling throughout the life cycle of T. cruzi, which shapes the physicochemical composition of the extracellular vesicles and could have an impact in the ability of these vesicles to participate in cell communication in completely different niches of infection. ; ERANet program ; Instituto Carlos III ; Ministerio de Sanidad, Gobierno de España ; Fundación Ramón Areces funded the projects: "Research in prevention of congenital Chagas disease: parasitological, placental and immunological markers" (ERANet17/ HLH-0142 (Cochaco) ; ERANE-LAC HD 328/2014) and "Interactoma de las exovesículas de T. cruzi y de los inmunocomplejos que forman con las células del hospedador: implicaciones en la patología de la enfermedad de Chagas (2019)" ; Ministerio de Ciencia y Tecnología of the government of Spain funded the project PGC2018-099424-B-I00

Probiotics, included in functional foods, nutritional supplements, or nutraceuticals, exhibit different beneficial effects on gut function. They are extensively used to improve the digestive processes as well as reduce the symptoms and progression of different diseases. Probiotics have shown to improve dysbiosis and modulate the immune response of the host by interacting with different cell types. Probiotics and the host can interact in a direct way, but it is becoming apparent that communication occurs also through extracellular vesicles (EVs) derived from probiotics. EVs are key for bacteria–bacteria and bacteria–host interactions, since they carry a wide variety of components that can modulate different signaling pathways, including those involved in the immune response. Interestingly, EVs are recently starting to be considered as an alternative to probiotics in those cases for which the use of live bacteria could be dangerous, such as immunocompromised individuals or situations where the intestinal barrier is impaired. EVs can spread through the mucus layer and interact with the host, avoiding the risk of sepsis. This review summarizes the existing knowledge about EVs from different probiotic strains, their properties, and their potential use for the prevention or treatment of different gastrointestinal diseases. ; This work was supported by Junta de Andalucia (Spain) (research grants CTS 164 and PI-0206-2016) and the Spanish Ministry of Economy and Competitiveness (research grant AGL2015-67995-C3-3-R) and cofinanced by the Fondo Europeo de Desarollo Regional (FEDER) from the European Union. JA-MT is a Ph.D. student from the Postgraduate Program Nutricion y Ciencias de los Alimentos at the University of Granada (Spain). The CIBER-EHD is funded by the Instituto de Salud Carlos III.

Extracellular vesicles (EVs) transport biological content between cells to mediate physiological processes. The association between EVs and resilience, the ability to cope with stress, is unknown. Using unbiased machine learning approaches, we aimed to identify a biological profile of resilience. Twenty servicemen (27.8 ± 5.9 years) completed the Connor Davidson Resilience (CD‐RISC) questionnaire and were exposed to daily physical and cognitive exertion with 48‐hr sleep and caloric restriction. Blood samples from baseline and the second day of stress were analyzed for neuroendocrine biomarkers impacted by military stress. EVs were isolated from plasma and stained with antibodies associated with exosomes (CD63), microvesicles (VAMP3), and apoptotic bodies (THSD1). Individuals were separated into high (n = 10, CD‐RISC > 90) and low (n = 10, CD‐RISC < 79) resilience. EV features were stratified by size, then down‐selected using regression trees and compared between groups. Diagnostic accuracy was assessed using receiver operating characteristic curves. Compared to low resilience, high resilience demonstrated a greater increase in variability of THSD1 local bright spot intensities among large‐sized EVs in response to stress (p = 0.002, Hedges' g = 1.59). Among medium‐sized EVs, high resilience exhibited a greater decrease in side scatter intensity (p = 0.014, Hedges' g = 1.17). Both features demonstrated high to moderate diagnostic accuracy for high resilience (AUC = 0.90 and 0.79). In contrast, neuroendocrine biomarker concentrations were similar between groups. The increase in variability among THSD1 + EVs in high, but not low, resilient individuals following stress may suggest high resilience is accompanied by stress‐triggered apoptotic adaptations to the environment that are not detected in neuroendocrine biomarkers.