scholarly journals Gap junctional protein Cx43 is involved in the communication between extracellular vesicles and mammalian cells

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Ana Rosa Soares ◽  
Tania Martins-Marques ◽  
Teresa Ribeiro-Rodrigues ◽  
Joao Vasco Ferreira ◽  
Steve Catarino ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Mammalian Cells ◽  
Connexin 43 ◽  
Biological Effects ◽  
Biological Information ◽  
Target Cells ◽  
New Paradigm ◽  
Donor And Acceptor ◽  
Messenger Molecules

Abstract Intercellular communication is vital to ensure tissue and organism homeostasis and can occur directly, between neighbour cells via gap junctions (GJ), or indirectly, at longer distances, through extracellular vesicles, including exosomes. Exosomes, as intercellular carriers of messenger molecules, mediate the transfer of biological information between donor and acceptor cells. Although the biological effects of exosomes in target cells have been intensively studied, the mechanisms that govern exosomal uptake are not fully understood. Here, we show that Connexin 43 (Cx43), the most widely expressed GJ protein, is present in exosomes in the form of hexameric channels and, more importantly, that exosomal Cx43 is able to modulate the interaction and transfer of information between exosomes and acceptor cells. This study envisions a new paradigm where Cx43-containing channels mediate the release of exosomal content into cells, which constitutes a novel and unanticipated mechanism to modulate intercellular communication.

scholarly journals Myocardial infarction affects Cx43 content of extracellular vesicles secreted by cardiomyocytes

2020 ◽  
Vol 3 (12) ◽  
pp. e202000821
Author(s):  
Tania Martins-Marques ◽  
Teresa Ribeiro-Rodrigues ◽  
Saskia C de Jager ◽  
Monica Zuzarte ◽  
Cátia Ferreira ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Connexin 43 ◽  
Extracellular Vesicle ◽  
Therapeutic Strategies ◽  
Target Cells ◽  
Comprehensive Strategy ◽  
Junction Protein ◽  
Gap Junction Protein

Ischemic heart disease has been associated with an impairment on intercellular communication mediated by both gap junctions and extracellular vesicles. We have previously shown that connexin 43 (Cx43), the main ventricular gap junction protein, assembles into channels at the extracellular vesicle surface, mediating the release of vesicle content into target cells. Here, using a comprehensive strategy that included cell-based approaches, animal models and human patients, we demonstrate that myocardial ischemia impairs the secretion of Cx43 into circulating, intracardiac and cardiomyocyte-derived vesicles. In addition, we show that ubiquitin signals Cx43 release in basal conditions but appears to be dispensable during ischemia, suggesting an interplay between ischemia-induced Cx43 degradation and secretion. Overall, this study constitutes a step forward for the characterization of the signals and molecular players underlying vesicle protein sorting, with strong implications on long-range intercellular communication, paving the way towards the development of innovative diagnostic and therapeutic strategies for cardiovascular disorders.

scholarly journals Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Epithelial–Mesenchymal Transition

2019 ◽  
Vol 20 (19) ◽  
pp. 4813 ◽  
Author(s):  
Sevindzh Kletukhina ◽  
Olga Neustroeva ◽  
Victoria James ◽  
Albert Rizvanov ◽  
Marina Gomzikova
Keyword(s):  
Epithelial Cells ◽  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Epithelial Mesenchymal Transition ◽  
Genetic Material ◽  
Biologically Active ◽  
Target Cells ◽  
Mesenchymal Transition ◽  
New Evidence

Epithelial–mesenchymal transition (EMT) is a process that takes place during embryonic development, wound healing, and under some pathological processes, including fibrosis and tumor progression. The molecular changes occurring within epithelial cells during transformation to a mesenchymal phenotype have been well studied. However, to date, the mechanism of EMT induction remains to be fully elucidated. Recent findings in the field of intercellular communication have shed new light on this process and indicate the need for further studies into this important mechanism. New evidence supports the hypothesis that intercellular communication between mesenchymal stroma/stem cells (MSCs) and resident epithelial cells plays an important role in EMT induction. Besides direct interactions between cells, indirect paracrine interactions by soluble factors and extracellular vesicles also occur. Extracellular vesicles (EVs) are important mediators of intercellular communication, through the transfer of biologically active molecules, genetic material (mRNA, microRNA, siRNA, DNA), and EMT inducers to the target cells, which are capable of reprogramming recipient cells. In this review, we discuss the role of intercellular communication by EVs to induce EMT and the acquisition of stemness properties by normal and tumor epithelial cells.

scholarly journals Extracellular Vesicles Orchestrate Immune and Tumor Interaction Networks

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3696
Author(s):  
Kevin Ho Wai Yim ◽  
Ala’a Al Hrout ◽  
Simone Borgoni ◽  
Richard Chahwan
Keyword(s):  
Communication Networks ◽  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Potential Role ◽  
Viral Infections ◽  
Biological Effects ◽  
Surface Markers ◽  
Physiological Conditions ◽  
Intercellular Communications

Extracellular vesicles (EVs) are emerging as potent and intricate intercellular communication networks. From their first discovery almost forty years ago, several studies have bolstered our understanding of these nano-vesicular structures. EV subpopulations are now characterized by differences in size, surface markers, cargo, and biological effects. Studies have highlighted the importance of EVs in biology and intercellular communication, particularly during immune and tumor interactions. These responses can be equally mediated at the proteomic and epigenomic levels through surface markers or nucleic acid cargo signaling, respectively. Following the exponential growth of EV studies in recent years, we herein synthesize new aspects of the emerging immune–tumor EV-based intercellular communications. We also discuss the potential role of EVs in fundamental immunological processes under physiological conditions, viral infections, and tumorigenic conditions. Finally, we provide insights on the future prospects of immune–tumor EVs and suggest potential avenues for the use of EVs in diagnostics and therapeutics.

scholarly journals Role of microRNA Shuttled in Small Extracellular Vesicles Derived From Mesenchymal Stem/Stromal Cells for Osteoarticular Disease Treatment

2021 ◽  
Vol 12 ◽  
Author(s):  
Eliana Lara-Barba ◽  
María Jesús Araya ◽  
Charlotte Nicole Hill ◽  
Felipe A. Bustamante-Barrientos ◽  
Alexander Ortloff ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Gene Expression Regulation ◽  
Biological Effects ◽  
Experimental Studies ◽  
Tumor Formation ◽  
Target Cells ◽  
Therapeutic Effects ◽  
Age Related ◽  
Current Therapies

Osteoarticular diseases (OD), such as rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic autoimmune/inflammatory and age-related diseases that affect the joints and other organs for which the current therapies are not effective. Cell therapy using mesenchymal stem/stromal cells (MSCs) is an alternative treatment due to their immunomodulatory and tissue differentiation capacity. Several experimental studies in numerous diseases have demonstrated the MSCs’ therapeutic effects. However, MSCs have shown heterogeneity, instability of stemness and differentiation capacities, limited homing ability, and various adverse responses such as abnormal differentiation and tumor formation. Recently, acellular therapy based on MSC secreted factors has raised the attention of several studies. It has been shown that molecules embedded in extracellular vesicles (EVs) derived from MSCs, particularly those from the small fraction enriched in exosomes (sEVs), effectively mimic their impact in target cells. The biological effects of sEVs critically depend on their cargo, where sEVs-embedded microRNAs (miRNAs) are particularly relevant due to their crucial role in gene expression regulation. Therefore, in this review, we will focus on the effect of sEVs derived from MSCs and their miRNA cargo on target cells associated with the pathology of RA and OA and their potential therapeutic impact.

Role of connexin 43 in different forms of intercellular communication – gap junctions, extracellular vesicles and tunnelling nanotubes

2017 ◽  
Vol 130 (21) ◽  
pp. 3619-3630 ◽  
Author(s):  
Teresa M. Ribeiro-Rodrigues ◽  
Tânia Martins-Marques ◽  
Sandrine Morel ◽  
Brenda R. Kwak ◽  
Henrique Girão
Keyword(s):  
Gap Junctions ◽  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Connexin 43 ◽  
Communication Gap

scholarly journals Micro RNAs are minor constituents of extracellular vesicles and are hardly delivered to target cells

2020 ◽  
Author(s):  
Manuel Albanese ◽  
Yen-Fu Adam Chen ◽  
Corinna Hüls ◽  
Kathrin Gärtner ◽  
Takanobu Tagawa ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mammalian Cells ◽  
Cell Communication ◽  
Cell Types ◽  
Convincing Evidence ◽  
Target Cells ◽  
Mrna Targets ◽  
Negative Results ◽  
Micro Rnas ◽  
Different Types

ABSTRACTMammalian cells release different types of vesicles, collectively termed extracellular vesicles (EVs). EVs contain cellular microRNAs (miRNAs) with an apparent potential to deliver their miRNA cargo to recipient cells to affect the stability of individual mRNAs and the cells’ transcriptome. The extent to which miRNAs are exported via the EV route and whether they contribute to cell-cell communication are controversial. To address these issues, we analyzed the capacity of EVs to deliver packaged miRNAs into target cells and to exert biological functions. We applied well-defined approaches to produce and characterize purified EVs with or without specific viral miRNAs. We found that only a small fraction of EVs carried miRNAs. EVs readily bound to different target cell types, but there was no EV-cell membrane fusion or delivery of cargo. Importantly, the functionality of cells exposed to miRNA-carrying EVs was not affected. These results suggest EV-borne miRNAs do not act as effectors and question their relevancy in paracrine cell-to-cell communication.AUTHOR SUMMARYThe majority of metazoan cells release vesicles of different types and origins, such as exosomes and microvesicles, now collectively termed extracellular vesicles (EVs). EVs have gained much attention because they contain microRNAs (miRNAs) and thus could regulate their specific mRNA targets in recipient or acceptor cells that take up EVs. Using a novel fusion assay with superior sensitivity and specificity, we revisited this claim but found no convincing evidence for an efficient functional uptake of EVs in many different cell lines and primary human blood cells. Even EVs engineered to fuse and deliver their miRNA cargo to recipient cells had no measurable effect on target mRNAs in very carefully controlled, quantitative experiments. Our negative results clearly indicate that EVs do not act as vehicles for miRNA-based cell-to-cell communication.

scholarly journals MicroRNAs are minor constituents of extracellular vesicles that are rarely delivered to target cells

PLoS Genetics ◽  
2021 ◽  
Vol 17 (12) ◽  
pp. e1009951
Author(s):  
Manuel Albanese ◽  
Yen-Fu Adam Chen ◽  
Corinna Hüls ◽  
Kathrin Gärtner ◽  
Takanobu Tagawa ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Target Cell ◽  
Mammalian Cells ◽  
Cell Communication ◽  
Cell Types ◽  
Target Cells ◽  
Messenger Rnas ◽  
Biological Functions ◽  
Different Types ◽  
The Stability

Mammalian cells release different types of vesicles, collectively termed extracellular vesicles (EVs). EVs contain cellular microRNAs (miRNAs) with an apparent potential to deliver their miRNA cargo to recipient cells to affect the stability of individual mRNAs and the cells’ transcriptome. The extent to which miRNAs are exported via the EV route and whether they contribute to cell-cell communication are controversial. To address these issues, we defined multiple properties of EVs and analyzed their capacity to deliver packaged miRNAs into target cells to exert biological functions. We applied well-defined approaches to produce and characterize purified EVs with or without specific viral miRNAs. We found that only a small fraction of EVs carried miRNAs. EVs readily bound to different target cell types, but EVs did not fuse detectably with cellular membranes to deliver their cargo. We engineered EVs to be fusogenic and document their capacity to deliver functional messenger RNAs. Engineered fusogenic EVs, however, did not detectably alter the functionality of cells exposed to miRNA-carrying EVs. These results suggest that EV-borne miRNAs do not act as effectors of cell-to-cell communication.

scholarly journals Trichomonas vaginalis extracellular vesicles are internalized by host cells using proteoglycans and caveolin-dependent endocytosis

2019 ◽  
Vol 116 (43) ◽  
pp. 21354-21360 ◽  
Author(s):  
Anand Kumar Rai ◽  
Patricia J. Johnson
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Extracellular Vesicles ◽  
Mammalian Cells ◽  
Trichomonas Vaginalis ◽  
Host Cells ◽  
Titration Calorimetry ◽  
Mammalian Host ◽  
Target Cells ◽  
Host Cell Surface

Trichomonas vaginalis, a human-infective parasite, causes the most prevalent nonviral sexually transmitted infection worldwide. This pathogen secretes extracellular vesicles (EVs) that mediate its interaction with host cells. Here, we have developed assays to study the interface between parasite EVs and mammalian host cells and to quantify EV internalization by mammalian cells. We show that T. vaginalis EVs interact with glycosaminoglycans on the surface of host cells and specifically bind to heparan sulfate (HS) present on host cell surface proteoglycans. Moreover, competition assays using HS or removal of HS from the host cell surface strongly inhibit EV uptake, directly demonstrating that HS proteoglycans facilitate EV internalization. We identified an abundant protein on the surface of T. vaginalis EVs, 4-α-glucanotransferase (Tv4AGT), and show using isothermal titration calorimetry that this protein binds HS. Tv4AGT also competitively inhibits EV uptake, defining it as an EV ligand critical for EV internalization. Finally, we demonstrate that T. vaginalis EV uptake is dependent on host cell cholesterol and caveolin-1 and that internalization proceeds via clathrin-independent, lipid raft-mediated endocytosis. These studies reveal mechanisms used to drive host:pathogen interactions and further our understanding of how EVs are internalized by target cells to allow cross-talk between different cell types.

scholarly journals Extracellular Vesicles: Overview and Clinical Implications

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. SCI-25-SCI-25
Author(s):  
Francoise Dignat-George
Keyword(s):  
Extracellular Vesicles ◽  
Conflicts Of Interest ◽  
Current Knowledge ◽  
Body Fluids ◽  
Biological Information ◽  
Current Debate ◽  
Target Cells ◽  
Biological Functions ◽  
Disease Evolution ◽  
Methodological Guidelines

Abstract The release of extracellular vesicles (EVs) is a phenomenon shared by all cell types as a means of communication. Characterization and classification of EVs is challenging and still a matter of debate. However, a general consensus on EVs nomenclatura has been made, on the basis of their size, formation and release mechanisms. EVs has been classified into exosomes, secreted via exocytosis from the late endosome multivesicular bodies, whereas microvesicles (MVs) bud from the plasma membrane and apoptotic bodies are released by cells undergoing apoptosis. Initially regarded as cellular debris, EVs have gained considerable interest in basic sciences and medical research, both as biomarkers and mediators of biological functions. Indeed, EVs carry regulatory molecules including lipid, proteins and different RNA species through the extracellular spaces and deliver these cargos to target cells to modify cellular activity, thereby contributing to both physiological and pathological responses. Because EVs bear markers derived from their parent cells and can be detected in most body fluids, characterization of EVs of different cellular origin is an underestimated source of biological information on cellular activation during disease evolution, and will probably serve as valuable diagnostic and prognostic biomarker in the future. However, the current methods used for the EVs isolation and analysis have several limitations and lack standardization, leading to uncertainties regarding the subtypes of EVs studied and how to interpret the data. After a rapid overview of the current knowledge on the mechanisms of formation, subcellular origin and composition of the different types of EVs, this presentation will focus on microvesicles (MVs). We will first address how their structure/function diversity determines their multifaceted biological functions in coagulation, inflammation, angiogenesis and endothelial dysfunction (ref 1, 2, 3). Secondly, we will summarize the current debate on the different methodologies available for their analysis and quantification in body fluids. A specific attention will be devoted to standardization of sample processing and MVs analysis, and also to recommendations from scientific societies for EVs translational applications as emerging biomarkers measurable in liquid biopsies (ref 4, 5, 6). Finally, focusing on cardiovascular diseases and cancer as emerging field where MVs detection have promising impact to improve patient management, we will illustrate how combination of increasing fundamental knowledge, technological progress and standardization will push MVs towards reliable biomarkers ready for the clinics. 1- Ridger VC, Boulanger CM, Angelillo-Scherrer A, Badimon L, Blanc-Brude O, Bochaton-Piallat ML, Boilard E, Buzas EI, Caporali A, Dignat-George F, Evans PC, Lacroix R, Lutgens E, Ketelhuth DFJ, Nieuwland R, Toti F, Tunon J, Weber C, Hoefer IE. Microvesicles in vascular homeostasis and diseases. Position Paper of the European Society of Cardiology (ESC) Working Group on Atherosclerosis and Vascular Biology. Thromb Haemost. 2017;28;117(7):1296-1316. 2- Todorova D, Simoncini S, Lacroix R, Sabatier F, Dignat-George F. Extracellular Vesicles in Angiogenesis. Circ Res. 2017;12;120(10):1658-1673. 3- Lacroix R, Dubois C, Leroyer AS, Sabatier F, Dignat-George F. Revisited role of microparticles in arterial and venous thrombosis. J Thromb Haemost. 2013;11 Suppl 1:24-35. 4- Coumans FAW, Brisson AR, Buzas EI, Dignat-George F, Drees EEE, El-Andaloussi S, Emanueli C, Gasecka A, Hendrix A, Hill AF, Lacroix R, Lee Y, van Leeuwen TG, Mackman N, Mäger I, Nolan JP, van der Pol E, Pegtel DM, Sahoo S, Siljander PRM, Sturk G, de Wever O, Nieuwland R. Methodological Guidelines to Study Extracellular Vesicles. Circ Res. 2017;12;120(10):1632-1648. 5-Lacroix R, Judicone C, Mooberry M, Boucekine M, Key NS, Dignat-George F; The ISTH SSC Workshop. Standardization of pre-analytical variables in plasma microparticle determination: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. J Thromb Haemost. 2013 Apr 2. 6- Cointe S, Judicone C, Robert S, Mooberry MJ, Poncelet P, Wauben M, Nieuwland R, Key NS, Dignat-George F, Lacroix R. Standardization of microparticle enumeration across different flow cytometry platforms: results of a multicenter collaborative workshop. J Thromb Haemost. 2017;15(1):187-193. Disclosures No relevant conflicts of interest to declare.

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