DOCSLIB.ORG

Macrophage-Derived Microvesicles' Pathogenic Role in Acute Lung Injury

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Macrophage-Derived Microvesicles' Pathogenic Role in Acute Lung Injury Thorax Online First, published on August 18, 2016 as 10.1136/thoraxjnl-2016-208895 Editorial ’ the MVs were isolated during the course Thorax: first published as 10.1136/thoraxjnl-2016-208895 on 18 August 2016. Downloaded from Macrophage-derived microvesicles of ALI. And lastly, although the protein cargoes of MVs are important, the role of pathogenic role in acute lung injury mRNA and microRNA in the MVs should not be overlooked. Multiple studies have Jae W Lee shown a transfer of the RNA content between MVs and cells with subsequent translation of the mRNA or microRNA Once considered cellular debris or, more mechanisms of MVs, the authors found leading to a functional effect.2310In the recently, as biomarkers of disease progres- that MVs released by primary cultures of current study, the inflammatory response sion, extracellular vesicles (EVs), com- mouse macrophages primed with LPS to following MVs’ administration in vivo or prised of exosomes, microvesicles (MVs) obtain a pro-inflammatory phenotype also in vitro may be artificially diminished due and apoptotic bodies, released by living induced ICAM-1 expression in MLE-12 to the short incubation time (4 hours), and dying eukaryotic cells are now recog- cells, which was dependent on the TNF which may not be enough for the transla- nised as important mediators of cellular cargo of the MVs. When instilled intratra- tion of the RNA cargo. One wonders, if communication and function.1 EVs are a cheally in naive mice, MVs isolated from the incubation time was increased, heterogeneous population of anucleate macrophages primed with LPS induced whether the inflammatory response would vesicles with a diameter of 100–1000 nm ALI with an increase in influx of neutro- be greater. that are released from intracellular com- phils and cytokines/chemokines (eg, KC), As with any manuscript with findings partments as exosomes or by budding off in lung protein permeability and in the with potential translational impact, more the plasma membrane as MVs in response expression of ICAM-1 on alveolar epithe- questions are raised than answered. How to diverse physiological, pathophysio- lial type I and II cells (Figure 8).7 critical are MVs, exosomes and apoptotic logical or external stimulus. Despite its There are several important findings in bodies in the pathophysiology of ALI importance in various organ injuries and the manuscript by Soni et al7 with clinical compared with the released soluble cancer,23the role of EVs in the pathogen- relevance. First, the clear demonstration factors, for example, cytokines and che- esis of acute lung injury (ALI) is still that MVs released into the injured alveo- mokines, especially in terms of the early – largely unexplored.4 6 In the current issue lus early in ALI were biologically active, inflammatory phase? Soni et al7 found of Thorax, Soni et al7 studied the tem- with the capability to induce an inflamma- minimal levels of IL-1β and IL-6, inflam- poral pattern of EV release in early ALI tory response. All experiments had appro- matory cytokines with significant inflam- and found that MVs from alveolar macro- priate controls such as MVs isolated from matory roles in ALI, in the MVs derived phages were the predominant source and the BALF from mice without injury or the predominantly from alveolar macro- played a significant role as potent initia- supernatant from the washing steps phages. However, Eltom et al and others tors of the inflammatory response in part during the isolation of the MVs as well as have shown that increased airway ATP by the transfer of its cargo, the cytokine low and high doses of LPS to ensure the levels, commonly found in patients with tumour necrosis factor (TNF), to target inflammatory response was specific to the respiratory diseases such as asthma and cells. MVs, not contaminants. Second, in early COPD, can stimulate the release of IL-1β/ http://thorax.bmj.com/ By inducing ALI with intratracheal ALI following intratracheal LPS instilla- IL-18 from EVs released during infec- instillation of lipopolysaccharide (LPS) in tion, alveolar macrophages were the initial tion.11 Can MVs, exosomes or apoptotic C57BL6 mice, the authors found that source of the pro-inflammatory MVs, fol- bodies be targeted and neutralised during MVs released into the injured alveolus lowed soon thereafter by MVs released the early inflammatory phase of ALI, pos- were mainly from alveolar macrophages from alveolar epithelial cells and neutro- sibly preventing the progression to acute initially by flow cytometry, peaking at phils, as determined by flow cytometry. respiratory distress syndrome? Will the 1 hour and followed soon thereafter by And finally, the protein cargo, for molecular cargo of the released MVs, exo- MVs released by alveolar epithelial cells example, TNF, was one of the mechan- somes or apoptotic bodies differ based on on October 2, 2021 by guest. Protected copyright. and neutrophils by 4 hours. More import- isms through which MVs induced an the cause of ALI, for example, LPS versus antly, the MVs in the bronchoalveolar inflammatory response. bacterial pneumonia versus sepsis versus fluid (BALF) at 1 hour contained a sub- There are limitations to the manuscript ventilator-induced lung injury? For stantial amount of TNF but low levels of that require further study to more clearly example, are EVs released by endothelial interleukin (IL)-1β and IL-6 and induced define the role of EVs released during cells potentially more critical in indirect a mouse lung epithelial (MLE)-12 cell line ALI. In the context of early ALI, what are ALI such as following abdominal sepsis to express intercellular adhesion molecule the roles of exosomes or apoptotic bodies for the initiation of the inflammatory 1 (ICAM-1) and secrete KC, a murine in the inflammatory response? What response in the lung12? Although the IL-8 homologue, at 4 hours. Surprisingly, about other cellular sources such as plate- focus of the current study was on MVs alveolar LPS-generated MVs were almost lets, which are a major source of EVs and derived from alveolar macrophages, twice more potent than a dose of LPS play a critical role in ALI?8 The pheno- clearly MVs derived from neutrophils (100 mg/mL) used as a positive control type of the cells may determine the func- have significant roles during ALI. Timár group on the expression of ICAM-1 and tional effects of the released MVs. For et al13 recently found that MVs released secretion of KC by MLE-2 cells example, several studies have shown a key from primary cultures of human neutro- (Figure 6). In experiments to study the role of alveolar macrophages with an anti- phils had bacteriostatic properties. And as inflammatory M2 phenotype in the reso- alluded to as a limitation, the number and lution of ALI.9 The functional effect of phenotype of the EVs will markedly Correspondence to Dr Jae-W Lee, Department of Anesthesiology, University of California San Francisco, the released MV from alveolar macro- change prior to, during and in the reso- 505 Parnassus Ave., P. O. Box 0648, San Francisco, phages may be both pro-inflammatory and lution phase of ALI. Using surface mem- CA 94143, USA; [email protected] anti-inflammatory, depending on when brane markers to identify the source of Lee JW. Thorax Month 2016 Vol 0 No 0 1 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& BTS) under licence. Editorial fl the MVs by ow cytometry may be inad- 8 Yadav H, Kor DJ. Platelets in the pathogenesis of Thorax: first published as 10.1136/thoraxjnl-2016-208895 on 18 August 2016. Downloaded from equate in describing the biological role of acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 2015;309:L915–923. these vesicles. Clearly, more studies are 9D’Alessio FR, Craig JM, Singer BD, et al. Enhanced required and new techniques may need to resolution of experimental ARDS through IL-4- be developed. mediated lung macrophage reprogramming. Am ▸ Despite extensive research and numer- http://dx.doi.org/10.1136/thoraxjnl-2015-208032 J Physiol Lung Cell Mol Physiol 2016;310:L733–46. 10 Zhu YG, Feng XM, Abbott J, et al. Human ous preclinical studies identifying various Thorax 2016;0:1–2. fi mesenchymal stem cell microvesicles for treatment of biological mediators, there are no speci c doi:10.1136/thoraxjnl-2016-208895 Escherichia coli endotoxin-induced acute lung injury pharmacological therapies for acute in mice. Stem Cells 2014;32:116–25. respiratory distress syndrome, the clinical REFERENCES 11 Eltom S, Dale N, Raemdonck KRG, et al. Respiratory form of ALI, and treatment is largely 1 Witwer KW, Buzás EI, Bemis LT, et al. infections cause the release of extracellular veiscles: implications in exacerbation of asthma/COPD. PLoS limited to supportive care and lung- Standardization of sample collection, isolation and 14–16 analysis methods in extracellular vesicle research. ONE 2014;9:e101087. protective ventilation. The manu- J Extracell Vesicles 2013;2:20360. 12 Letsiou E, Sammani S, Zhang W, et al. Pathologic script by Soni et al adds to the under- 2 Das S, Halushka MK. Extracellular vesicle microRNA mechanical stress and endotoxin exposure increases standing of the biological role of EVs in transfer in cardiovascular disease. Cardiovasc Pathol lung endothelial microparticle shedding. Am J Respir – the pathophysiology of acute respiratory 2015;24:199–206. Cell Mol Biol 2015;52:193 204. 13 Timár CI, Lorincz AM, Csépányi-Kömi R, et al. distress syndrome, which may ultimately 3 Kalluri R. The biology and function of exosomes in cancer. J Clin Invest 2016;126:1208–15. Antibacterial effect of microvesicles released from yield new therapeutic targets and reinvig- 4 McVey M, Tabuchi A, Kuebler WM.
Load more

Recommended publications
  • Caveolin-1 Selectively Regulates Microrna Sorting Into Microvesicles After Noxious Stimuli
    Published Online: 24 June, 2019 | Supp Info: http://doi.org/10.1084/jem.20182313 Downloaded from jem.rupress.org on October 1, 2019 ARTICLE Caveolin-1 selectively regulates microRNA sorting into microvesicles after noxious stimuli Heedoo Lee1, Chunhua Li2, Yang Zhang2, Duo Zhang1, Leo E. Otterbein3, and Yang Jin1 Emerging evidence suggests that extracellular vesicle (EV)–containing miRNAs mediate intercellular communications in response to noxious stimuli. It remains unclear how a cell selectively sorts the cellular miRNAs into EVs. We report that caveolin-1 (cav-1) is essential for sorting of selected miRNAs into microvesicles (MVs), a main type of EVs generated by outward budding of the plasma membrane. We found that cav-1 tyrosine 14 (Y14)–phosphorylation leads to interactions between cav-1 and hnRNPA2B1, an RNA-binding protein. The cav-1/hnRNPA2B1 complex subsequently traffics together into MVs. Oxidative stress induces O-GlcNAcylation of hnRNPA2B1, resulting in a robustly altered hnRNPA2B1-bound miRNA repertoire. Notably, cav-1 pY14 also promotes hnRNPA2B1 O-GlcNAcylation. Functionally, macrophages serve as the principal recipient of epithelial MVs in the lung. MV-containing cav-1/hnRNPA2B1 complex-bound miR-17/93 activate tissue macrophages. Collectively, cav-1 is the first identified membranous protein that directly guides RNA-binding protein into EVs. Our work delineates a novel mechanism by which oxidative stress compels epithelial cells to package and secrete specific miRNAs and elicits an innate immune response. Introduction Extracellular vesicles (EVs) have been shown to transfer func- This process involves an ATP-dependent, active sorting mech- tional miRNAs to neighboring or distant recipient cells as a rapid anism (Xu et al., 2013) and involves RNA-binding proteins that modality by which to manipulate gene expression in the recip- are enriched in EVs (Laffont et al., 2013; Villarroya-Beltri et al., ient cells (Phinney et al., 2015; Shipman, 2015).
    [Show full text]
  • Adenine-Based Purines and Related Metabolizing Enzymes: Evidence for Their Impact on Tumor Extracellular Vesicle Activities
    cells Review Adenine-Based Purines and Related Metabolizing Enzymes: Evidence for Their Impact on Tumor Extracellular Vesicle Activities Patrizia Di Iorio 1,2 and Renata Ciccarelli 1,2,* 1 Department of Medical, Oral and Biotechnological Sciences, ‘G. D’Annunzio’ University of Chieti-Pescara, 66100 Chieti, Italy; [email protected] 2 Center for Advanced Studies and Technology (CAST), ‘G. D’Annunzio’ University of Chieti-Pescara, 66100 Chieti, Italy * Correspondence: [email protected] Abstract: Extracellular vesicles (EVs), mainly classified as small and large EVs according to their size/origin, contribute as multi-signal messengers to intercellular communications in normal/pathological conditions. EVs are now recognized as critical players in cancer processes by promoting transformation, growth, invasion, and drug-resistance of tumor cells thanks to the release of molecules contained inside them (i.e., nucleic acids, lipids and proteins) into the tumor microenvironment (TME). Interestingly, secre- tion from donor cells and/or uptake of EVs/their content by recipient cells are regulated by extracellular signals present in TME. Among those able to modulate the EV-tumor crosstalk, purines, mainly the adenine-based ones, could be included. Indeed, TME is characterized by high levels of ATP/adenosine and by the presence of enzymes deputed to their turnover. Moreover, ATP/adenosine, interacting with their own receptors, can affect both host and tumor responses. However, studies on whether/how the purinergic system behaves as a modulator of EV biogenesis, release and functions in cancer are still poor. Thus, this review is aimed at collecting data so far obtained to stimulate further research in this regard.
    [Show full text]
  • Exosomes Or Microvesicles, a Secreted Subcellular Organelle Contributing to Inflammation and Diabetes
    2154 Diabetes Volume 67, November 2018 Exosomes or Microvesicles, a Secreted Subcellular Organelle Contributing to Inflammation and Diabetes Yang D. Dai1,2 and Peter Dias1 Diabetes 2018;67:2154–2156 | https://doi.org/10.2337/dbi18-0021 Type 1 and type 2 diabetes (T1D and T2D) are generally etc., represent a pool of mixed EVs, with each subspecies recognized as distinct disease entities based on the mech- having a different cargo and function. The cargo of the EVs anism of induction of disease: T1D results from low or no contains important complex molecules such as RNA, DNA, insulin production due to the gradual loss of cells that proteins, lipids, and carbohydrates. The ratio of each sub- produce insulin, whereas T2D is generally thought to occur species and their molecular content may vary depending on as a result of the body’s development of resistance to the physiological/pathological status of the parent cells and insulin. Although the events initiating T1D and T2D might tissues that release the EVs. Thus, EVs may potentially be be very different, the progression to diabetes and compli- a powerful source for noninvasive diagnosis of diseases (10). cations are similar and involve interactions between the The study by Freeman et al. (11) in this issue of immune system and the metabolic system. Notably, chronic Diabetes is unique in that it uses an ex vivo approach to inflammation is a shared manifestation of the two types study the role and mechanism of action of EVs derived of diabetes (1,2). Recently, secreted microvesicles, particu- from blood plasma of normal patients, patients with pre- larly exosomes, were suggested to be intermediates linking diabetes, and patients with diabetes in the development of inflammation to diabetes (3).
    [Show full text]
  • Lung Epithelial Cell–Derived Microvesicles Regulate Macrophage Migration Via Microrna-17/221–Induced Integrin B1 Recycling
    Lung Epithelial Cell−Derived Microvesicles Regulate Macrophage Migration via MicroRNA-17/221−Induced Integrin β1 Recycling This information is current as of September 26, 2021. Heedoo Lee, Duo Zhang, Jingxuan Wu, Leo E. Otterbein and Yang Jin J Immunol published online 3 July 2017 http://www.jimmunol.org/content/early/2017/07/01/jimmun ol.1700165 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/07/01/jimmunol.170016 Material 5.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published July 3, 2017, doi:10.4049/jimmunol.1700165 The Journal of Immunology Lung Epithelial Cell–Derived Microvesicles Regulate Macrophage Migration via MicroRNA-17/221–Induced Integrin b1 Recycling Heedoo Lee,* Duo Zhang,* Jingxuan Wu,* Leo E. Otterbein,† and Yang Jin* Robust lung inflammation is one of the prominent features in the pathogenesis of acute lung injury (ALI).
    [Show full text]
  • Emerging Role of Extracellular Vesicles in the Pathophysiology of Multiple Sclerosis
    International Journal of Molecular Sciences Review Emerging Role of Extracellular Vesicles in the Pathophysiology of Multiple Sclerosis 1, 1, 1,2, 1 Ettore Dolcetti y, Antonio Bruno y , Livia Guadalupi y, Francesca Romana Rizzo , Alessandra Musella 2,3, Antonietta Gentile 2, Francesca De Vito 4, Silvia Caioli 4, Silvia Bullitta 1,2, Diego Fresegna 2, Valentina Vanni 1,2, Sara Balletta 1, Krizia Sanna 1, Fabio Buttari 4, Mario Stampanoni Bassi 4 , Diego Centonze 1,4,* and Georgia Mandolesi 2,3 1 Synaptic Immunopathology Lab, Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy; [email protected] (E.D.); [email protected] (A.B.); [email protected] (L.G.); [email protected] (F.R.R.); [email protected] (S.B.); [email protected] (V.V.); [email protected] (S.B.); [email protected] (K.S.) 2 Synaptic Immunopathology Lab, IRCCS San Raffaele Pisana, 00163 Rome, Italy; [email protected] (A.M.); [email protected] (A.G.); [email protected] (D.F.); [email protected] (G.M.) 3 Department of Human Sciences and Quality of Life Promotion, University of Rome San Raffaele, 00163 Rome, Italy 4 Unit of Neurology, IRCCS Neuromed, Pozzilli (Is), 86077 Pozzilli, Italy; [email protected] (F.D.V.); [email protected] (S.C.); [email protected] (F.B.); [email protected] (M.S.B.) * Correspondence: [email protected]; Tel.:+39-06 7259-6010; Fax: +39-06-7259-6006 Co-first authors. y Received: 30 August 2020; Accepted: 1 October 2020; Published: 4 October 2020 Abstract: Extracellular vesicles (EVs) represent a new reality for many physiological and pathological functions as an alternative mode of intercellular communication.
    [Show full text]
  • Extracellular Vesicles: Mechanisms in Human Health and Disease Marine Malloci, Liliana Perdomo, Maëva Veerasamy, Ramaroson Andriantsitohaina, Gilles Simard, M
    Extracellular Vesicles: Mechanisms in Human Health and Disease Marine Malloci, Liliana Perdomo, Maëva Veerasamy, Ramaroson Andriantsitohaina, Gilles Simard, M. Carmen Martínez To cite this version: Marine Malloci, Liliana Perdomo, Maëva Veerasamy, Ramaroson Andriantsitohaina, Gilles Simard, et al.. Extracellular Vesicles: Mechanisms in Human Health and Disease. Antioxidants and Redox Signaling, Mary Ann Liebert, 2019, 30 (6), pp.813-856. 10.1089/ars.2017.7265. hal-02323323 HAL Id: hal-02323323 https://hal.archives-ouvertes.fr/hal-02323323 Submitted on 16 Dec 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Malloci COMPREHENSIVE INVITED REVIEW EXTRACELLULAR VESICLES: MECHANISMS IN HUMAN HEALTH AND DISEASE Marine Malloci1*, Liliana Perdomo1*, Maëva Veerasamy1, Ramaroson Andriantsitohaina1,2, Gilles Simard1,2, M. Carmen Martínez1,2 1INSERM UMR 1063, Stress oxydant et pathologies métaboliques, UNIV Angers, Université Bretagne Loire, F-49933, Angers, France; 2Centre Hospitalo-Universitaire d’Angers, F-49933, Angers, France *These authors contributed
    [Show full text]
  • Extracellular Vesicles in Innate Immune Cell Programming
    biomedicines Review Extracellular Vesicles in Innate Immune Cell Programming Naveed Akbar 1,* , Daan Paget 1,2 and Robin P. Choudhury 1 1 Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; [email protected] (D.P.); [email protected] (R.P.C.) 2 Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK * Correspondence: [email protected] Abstract: Extracellular vesicles (EV) are a heterogeneous group of bilipid-enclosed envelopes that carry proteins, metabolites, RNA, DNA and lipids from their parent cell of origin. They mediate cellular communication to other cells in local tissue microenvironments and across organ systems. EV size, number and their biologically active cargo are often altered in response to pathological processes, including infection, cancer, cardiovascular diseases and in response to metabolic pertur- bations such as obesity and diabetes, which also have a strong inflammatory component. Here, we discuss the broad repertoire of EV produced by neutrophils, monocytes, macrophages, their pre- cursor hematopoietic stem cells and discuss their effects on the innate immune system. We seek to understand the immunomodulatory properties of EV in cellular programming, which impacts innate immune cell differentiation and function. We further explore the possibilities of using EV as immune targeting vectors, for the modulation of the innate immune response, e.g., for tissue preservation during sterile injury such as myocardial infarction or to promote tissue resolution of inflammation and potentially tissue regeneration and repair. Keywords: exosomes; transcription; neutrophil; monocyte; hematopoietic stem cell Citation: Akbar, N.; Paget, D.; Choudhury, R.P. Extracellular Vesicles in Innate Immune Cell Programming.
    [Show full text]
  • Mesenchymal Stem Cell-Derived Microvesicles Improve Intestinal
    Zheng et al. Stem Cell Research & Therapy (2021) 12:299 https://doi.org/10.1186/s13287-021-02363-0 RESEARCH Open Access Mesenchymal stem cell-derived microvesicles improve intestinal barrier function by restoring mitochondrial dynamic balance in sepsis rats Danyang Zheng, Henan Zhou, Hongchen Wang, Yu Zhu, Yue Wu, Qinghui Li, Tao Li*† and Liangming Liu*† Abstract Background: Sepsis is a major cause of death in ICU, and intestinal barrier dysfunction is its important complication, while the treatment is limited. Recently, mesenchymal stem cell-derived microvesicles (MMVs) attract much attention as a strategy of cell-free treatment; whether MMVs are therapeutic in sepsis induced-intestinal barrier dysfunction is obscure. Methods: In this study, cecal ligation and puncture-induced sepsis rats and lipopolysaccharide-stimulated intestinal epithelial cells to investigate the effect of MMVs on intestinal barrier dysfunction. MMVs were harvested from mesenchymal stem cells and were injected into sepsis rats, and the intestinal barrier function was measured. Afterward, MMVs were incubated with intestinal epithelial cells, and the effect of MMVs on mitochondrial dynamic balance was measured. Then the expression of mfn1, mfn2, OPA1, and PGC-1α in MMVs were measured by western blot. By upregulation and downregulation of mfn2 and PGC-1α, the role of MMVs in mitochondrial dynamic balance was investigated. Finally, the role of MMV-carried mitochondria in mitochondrial dynamic balance was investigated. Results: MMVs restored the intestinal barrier function by improving mitochondrial dynamic balance and metabolism of mitochondria. Further study revealed that MMVs delivered mfn2 and PGC-1α to intestinal epithelial cells, and promoted mitochondrial fusion and biogenesis, thereby improving mitochondrial dynamic balance.
    [Show full text]
  • Microvesicles As Mediators of Intercellular Communication in Cancer—The Emerging Science of Cellular ‘Debris’
    Semin Immunopathol (2011) 33:455–467 DOI 10.1007/s00281-011-0250-3 REVIEW Microvesicles as mediators of intercellular communication in cancer—the emerging science of cellular ‘debris’ Tae Hoon Lee & Esterina D’Asti & Nathalie Magnus & Khalid Al-Nedawi & Brian Meehan & Janusz Rak Received: 11 January 2011 /Accepted: 13 January 2011 /Published online: 12 February 2011 # Springer-Verlag 2011 Abstract Cancer cells emit a heterogeneous mixture of Ongoing studies explore the molecular mechanisms and vesicular, organelle-like structures (microvesicles, MVs) mediators of MV-based intercellular communication (cancer into their surroundings including blood and body fluids. vesiculome) with the hope of using this information as a MVs are generated via diverse biological mechanisms possible source of therapeutic targets and disease biomarkers triggered by pathways involved in oncogenic transforma- in cancer. tion, microenvironmental stimulation, cellular activation, stress, or death. Vesiculation events occur either at the Keywords Angiogenesis . Biomarker . Cancer . Exosomes . plasma membrane (ectosomes, shed vesicles) or within Intercellular communication . Microvesicles . Oncogenes endosomal structures (exosomes). MVs are increasingly recognized as mediators of intercellular communication due Abbreviations to their capacity to merge with and transfer a repertoire of MVs Microvesicles bioactive molecular content (cargo) to recipient cells. Such TF Tissue factor processes may occur both locally and systemically, con- EGFR Epidermal growth factor receptor tributing to the formation of microenvironmental fields and EGFRvIII Mutant EGFR (variant III) niches. The bioactive cargo of MVs may include growth GBM Glioblastoma multiforme factors and their receptors, proteases, adhesion molecules, IL-6 Interleukin-6 signalling molecules, as well as DNA, mRNA, and micro- IL-8 Interleukin-8 RNA (miRs) sequences.
    [Show full text]
  • Exosomes and Microvesicles: an Introduction
    WHITEPAPER Exosomes and Microvesicles: An introduction Nanoparticle Tracking Analysis (NTA) Overview NTA utilizes the properties of both light scattering and Brownian motion in order to obtain the particle size distribution of samples in liquid suspension. A laser beam is passed through the sample chamber, and the particles in suspension in the path of this beam scatter light in such a manner that they can easily be visualized via a 20x magnification microscope onto which is mounted a camera. The camera, which operates at approximately 30 frames per second (fps), captures a video file of the particles moving under Brownian motion within the field of view of approximately 100 μm x 80 μm x 10 μm (Figure 1). Figure 1: Schematic of the optical configuration used in NTA. Malvern Instruments Worldwide Sales and service centres in over 65 countries www.malvern.com/contact ©2014 Malvern Instruments Limited WHITEPAPER The movement of the particles is captured on a frame-by-frame basis. The proprietary NTA software simultaneously identifies and tracks the center of each of the observed particles, and determines the average distance moved by each particle in the x and y planes. This value allows the particle diffusion coefficient (Dt) to be determined from which, if the sample temperature T and solvent viscosity η are known, the sphere- equivalent hydrodynamic diameter, d, of the particles can be identified using the Stokes-Einstein equation (Equation 1). where KB is Boltzmann’s constant. NTA is not an ensemble technique interrogating a very large number of particles, but rather each particle is sized individually, irrespective of the others.
    [Show full text]
  • Human Tumor-Released Microvesicles Promote the Differentiation of Myeloid Cells with Transforming Growth Factor-B–Mediated Suppressive Activity on T Lymphocytes
    Research Article Human Tumor-Released Microvesicles Promote the Differentiation of Myeloid Cells with Transforming Growth Factor-B–Mediated Suppressive Activity on T Lymphocytes Roberta Valenti,1 Veronica Huber,1 Paola Filipazzi,1 Lorenzo Pilla,1 Gloria Sovena,1 Antonello Villa,3,4 Alessandro Corbelli,2,3,4 Stefano Fais,5 Giorgio Parmiani,1 and Licia Rivoltini1 1Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori; 2Fondazione D’Amico, Milan, Italy; 3Microscopy and Image Analysis Consortium; 4Dipartimento di Neuroscienze e Tecnologie Biomediche, Universita` Milano-Bicocca, Monza, Italy; and 5Department of Drug Research and Evaluation, Section of Pharmacogenetic, Drug Resistance and Experimental Therapeutics, Istituto Superiore di Sanita`, Rome, Italy Abstract parental cell protein content and including molecules, such as Human tumors constitutively release endosome-derived HLA, tumor antigens, heat shock proteins, cytoskeleton compo- microvesicles, transporting a broad array of biologically nents, adhesion factors, etc. (1, 2, 4–6). active molecules with potential modulatory effects on differ- Although the extracellular release of membrane vesicles has been ent immune cells. Here, we report the first evidence that characterized under specific physiologic conditions in different tumor-released microvesicles alter myeloid cell function by normal cell types (including blood, endothelial, and epithelial cells), impairing monocyte differentiation into dendritic cells and the rate of shedding seems to be constitutive and markedly
    [Show full text]
  • Proteomic Comparison Defines Novel Markers to Characterize Heterogeneous Populations of Extracellular Vesicle Subtypes
    Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes Joanna Kowala, Guillaume Arrasb, Marina Colomboa, Mabel Jouvea, Jakob Paul Moratha, Bjarke Primdal-Bengtsona, Florent Dinglib, Damarys Loewb, Mercedes Tkacha, and Clotilde Thérya,1 aInstitut Curie, PSL Research University, INSERM U932, Department “Immunité et Cancer”, 75248 Paris, France; and bInstitut Curie, PSL Research University, Centre de Recherche, Laboratoire de Spectrométrie de masse Protéomique, 75248 Paris, France Edited by Randy Schekman, University of California, Berkeley, CA, and approved January 5, 2016 (received for review October 28, 2015) Extracellular vesicles (EVs) have become the focus of rising interest or recovered by high-speed ultracentrifugation (8), in the ab- because of their numerous functions in physiology and pathology. sence of demonstration of their intracellular origin. Such iso- Cells release heterogeneous vesicles of different sizes and intra- lation procedures coisolate mixed EV populations, which we will cellular origins, including small EVs formed inside endosomal call “small EVs” (sEVs), for lack of better term, in the rest of this compartments (i.e., exosomes) and EVs of various sizes budding article. Because EVs of different intracellular origins probably from the plasma membrane. Specific markers for the analysis and have different functional properties (9, 10), the mixed nature of isolation of different EV populations are missing, imposing EV preparations has made the growing literature increasingly important limitations to understanding EV functions. Here, EVs confusing, with contradictory proposed functions and clinical uses from human dendritic cells were first separated by their sedimen- of vesicles being regularly published. The lack of specific purifi- tation speed, and then either by their behavior upon upward cation and characterization tools prevents a clear understanding of floatation into iodixanol gradients or by immuno-isolation.
    [Show full text]