In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.

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Biological properties of extracellular vesicles and their physiological functions

Both eukaryotic and prokaryotic cells release small, phospholipid-enclosed vesicles into their environment. Why do cells release vesicles? Initial studies showed that eukaryotic vesicles are used to remove obsolete cellular molecules. Although this release of vesicles is beneficial to the cell, the vesicles can also be a danger to their environment, for instance in blood, where vesicles can provide a surface supporting coagulation. Evidence is accumulating that vesicles are cargo containers used by eukaryotic cells to exchange biomolecules as transmembrane receptors and genetic information. Because also bacteria communicate to each other via extracellular vesicles, the intercellular communication via extracellular cargo carriers seems to be conserved throughout evolution, and therefore vesicles are likely to be a highly efficient, robust, and economic manner of exchanging information between cells. Furthermore, vesicles protect cells from accumulation of waste or drugs, they contribute to physiology and pathology, and they have a myriad of potential clinical applications, ranging from biomarkers to anticancer therapy. Because vesicles may pass the blood-brain barrier, they can perhaps even be considered naturally occurring liposomes. Unfortunately, pathways of vesicle release and vesicles themselves are also being used by tumors and infectious diseases to facilitate spreading, and to escape from immune surveillance. In this review, the different types, nomenclature, functions, and clinical relevance of vesicles will be discussed.

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Classification, Functions, and Clinical Relevance of Extracellular Vesicles

Exosomes are 40-100-nm diameter membrane vesicles of endocytic origin that are released by most cell types upon fusion of multivesicular bodies with the plasma membrane, presumably as a vehicle for cell-free intercellular communication. While early studies focused on their secretion from diverse cell types in vitro, exosomes have now been identified in body fluids such as urine, amniotic fluid, malignant ascites, bronchoalveolar lavage fluid, synovial fluid, breast milk, saliva and blood. Exosomes have pleiotropic biological functions, including immune response, antigen presentation, intracellular communication and the transfer of RNA and proteins. While they have also been implicated in the transport and propagation of infectious cargo, such as prions, and retroviruses, including HIV, suggesting a role in pathological situations, recent studies suggest that the presence of such infectious cargo may be artefacts of exosome-purification strategies. Improvements in mass spectrometry-based proteomic tools, both hardware and software, coupled with improved purification schemes for exosomes, has allowed more in-depth proteome analyses, contributing immensely to our understanding of the molecular composition of exosomes. Proteomic cataloguing of exosomes from diverse cell types has revealed a common set of membrane and cytosolic proteins, suggesting the evolutionary importance of these membrane particles. Additionally, exosomes express an array of proteins that reflect the originating host cell. Recent findings that exosomes contain inactive forms of both mRNA and microRNA that can be transferred to another cell and be functional in that new environment, have initiated many microRNA profiling studies of exosomes circulating in blood. These studies highlight the potential of exosomal microRNA profiles for use as diagnostic biomarkers of disease through a noninvasive blood test. The exacerbated release of exosomes in tumor cells, as evidenced by their increased levels in blood during the late stage of a disease and their overexpression of certain tumor cell biomarkers, suggests an important role of exosomes in diagnosis and biomarker studies. The aim of this article is to provide a brief overview of exosomes, including methods used to isolate and characterize exosomes. New advances in proteomic methods, and both mass spectrometry hardware and informatics tools will be covered briefly.

Exosomes: proteomic insights and diagnostic potential

Owing to the relationship between extracellular vesicles (EVs) and physiological and pathological conditions, the interest in EVs is exponentially growing. EVs hold high hopes for novel diagnostic and translational discoveries. This review provides an expert-based update of recent advances in the methods to study EVs and summarizes currently accepted considerations and recommendations from sample collection to isolation, detection, and characterization of EVs. Common misconceptions and methodological pitfalls are highlighted. Although EVs are found in all body fluids, in this review, we will focus on EVs from human blood, not only our most complex but also the most interesting body fluid for cardiovascular research.

Methodological Guidelines to Study Extracellular Vesicles.

These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

Phospholipid composition of in vitro endothelial microparticles and their in vivo thrombogenic properties.

Cell-Derived Microparticles and Complement Activation in Preeclampsia Versus Normal Pregnancy

Background In Fabry disease, storage of globotriaosylceramide (Gb3) in arterial walls is one of the main pathogenetic factors that are thought to underlie the clinical manifestations of the disease. Abnormalities of the vessel wall, haemodynamics and pro- and anticoagulant factors may play a role, though the exact pathophysiology is incompletely understood. In this study, we try to clarify inconsistencies regarding coagulation activation, fibrinolysis, platelet activation and endothelial activation in 36 patients with Fabry disease. Methods Cell-derived microparticles, markers for coagulation activation (F(1+2), TAT, sTF, sEPCR), fibrinolysis (D-dimer, tPA, alpha(2)-AP), platelet activation (beta-TG, PF4), endothelial activation (vWF) and acute phase response (IL-6, CRP) were studied in relation to renal function and severity of the disease and compared to data from 36 age- and sex-matched healthy controls (17 males). Results Markers for endothelial activation and fibrinolysis were normal. Male patients had elevated levels of sTF and beta-TG, with an association between sTF and renal function and severity of the disease. In female patients, levels of TAT, beta-TG, PF4, CD63-positive platelet-derived microparticles and IL-6 were somewhat increased, with no correlation with renal function or disease severity. Conclusions Only minimal abnormalities in markers for platelet, endothelial activation and coagulation activation and fibrinolysis could be established in a large cohort of Fabry disease patients. The existing laboratory abnormalities are more likely related to renal insufficiency rather than to Fabry disease itself.

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Plasma markers of coagulation and endothelial activation in Fabry disease: impact of renal impairment*

Objectives To investigate whether cell-derived microparticles play a role in complement activation in pericardial blood of patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and whether microparticles in pericardial blood contribute to systemic complement activation upon retransfusion.Methods Pericardial blood of 13 patients was retransfused in 9 and discarded in 4 cases. Microparticles were isolated from systemic blood collected before anesthesia (T1) and at the end of CPB (T2), and from pericardial blood. The microparticles were analyzed by flow cytometry for bound complement components C1q, C4 and C3, and bound complement activator molecules C-reactive protein (CRP), serum amyloid P-component (SAP), immunoglobulin (Ig)M and IgG. Fluid-phase complement activation products (C4b/c, C3b/c) and activator molecules were determined by ELISA.Results Compared with systemic T1 blood, pericardial blood contained increased C4b/c and C3b/c, and increased levels of microparticles with bound comple...

Complement activation on the surface of cell-derived microparticles during cardiac surgery with cardiopulmonary bypass - is retransfusion of pericardial blood harmful?:

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarticular synovitis leading to cartilage, tendon and bone destruction, and pain and dysfunction of the joints. It is considered to be an immune-mediated inflammatory disorder, in which the complement system also plays a fundamental role. In the circulation of RA patients, increased levels of complement activation products have been found, often correlating with disease activity. In synovial fluid of the patients, decreased levels of native complement components and increased levels of activation products have been detected. Furthermore, in synovial tissue and cartilage, deposition of activated complement components has been demonstrated. As activators of the complement system in RA, immune complexes, C-reactive protein, and certain immunoglobulin G glycoforms have been identified. A role for complement activation in the pathogenesis of this disease is supported by studies showing an association between complement activation and inflammatory responses in the diseased joints or in individual cell types found in RA joints, and by extensive studies on animal models of the disease, utilizing for example animals deficient for certain complement components. Finally, several agents are under development to therapeutically influence the complement system, and some have already been tested in clinical trials of RA.

Targeting Complement in Rheumatoid Arthritis

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