Exosomes/microvesicles as a mechanism of cell-to-cell communication
2010; Elsevier BV; Volume: 78; Issue: 9 Linguagem: Inglês
10.1038/ki.2010.278
ISSN1523-1755
AutoresGiovanni Camussi, Maria Chiara Deregibus, Stefania Bruno, Vincenzo Cantaluppi, Luigi Biancone,
Tópico(s)Systemic Sclerosis and Related Diseases
ResumoMicrovesicles (MVs) are circular fragments of membrane released from the endosomal compartment as exosomes or shed from the surface membranes of most cell types. An increasing body of evidence indicates that they play a pivotal role in cell-to-cell communication. Indeed, they may directly stimulate target cells by receptor-mediated interactions or may transfer from the cell of origin to various bioactive molecules including membrane receptors, proteins, mRNAs, microRNAs, and organelles. In this review we discuss the pleiotropic biologic effects of MVs that are relevant for communication among cells in physiological and pathological conditions. In particular, we discuss their potential involvement in inflammation, renal disease, and tumor progression, and the evidence supporting a bidirectional exchange of genetic information between stem and injured cells. The transfer of gene products from injured cells may explain stem cell functional and phenotypic changes without the need of transdifferentiation into tissue cells. On the other hand, transfer of gene products from stem cells may reprogram injured cells to repair damaged tissues. Microvesicles (MVs) are circular fragments of membrane released from the endosomal compartment as exosomes or shed from the surface membranes of most cell types. An increasing body of evidence indicates that they play a pivotal role in cell-to-cell communication. Indeed, they may directly stimulate target cells by receptor-mediated interactions or may transfer from the cell of origin to various bioactive molecules including membrane receptors, proteins, mRNAs, microRNAs, and organelles. In this review we discuss the pleiotropic biologic effects of MVs that are relevant for communication among cells in physiological and pathological conditions. In particular, we discuss their potential involvement in inflammation, renal disease, and tumor progression, and the evidence supporting a bidirectional exchange of genetic information between stem and injured cells. The transfer of gene products from injured cells may explain stem cell functional and phenotypic changes without the need of transdifferentiation into tissue cells. On the other hand, transfer of gene products from stem cells may reprogram injured cells to repair damaged tissues. Cell-to-cell communication is required to guarantee proper coordination among different cell types within tissues. Cells may communicate by soluble factors,1.Majka M. Janowska-Wieczorek A. Ratajczak J. et al.Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner.Blood. 2001; 97: 3075-3085Crossref PubMed Scopus (314) Google Scholar adhesion molecule-mediated cell-to-cell interactions including cytonemes that connect neighboring cells enabling ligand–receptor-mediated transfer of surface-associated molecules, or by tunneling nanotubules that establish conduits between cells, allowing the transfer of not only surface molecules but also cytoplasmic components.2.Rustom A. Saffrich R. Markovic I. et al.Nanotubular highways for intercellular organelle transport.Science. 2004; 303: 1007-1010Crossref PubMed Scopus (546) Google Scholar, 3.Sherer N.M. Mothes W. Cytonemes and tunnelling nanotubules in cell-cell communication and viral pathogenesis.Trends Cell Biol. 2008; 18: 414-420Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar Recent studies have suggested that cells may also communicate by circular membrane fragments named microvesicles (MVs).4.Ratajczak J. Wysoczynski M. Hayek F. et al.Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication.Leukemia. 2006; 20: 1487-1495Crossref PubMed Scopus (443) Google Scholar For a long time, MVs were considered to be inert cellular debris, and the frequently observed vesicles by electron microscopy in the interstitial space of tissues or in blood were considered the consequence of cell damage or the result of dynamic plasmamembrane turnover.5.Siekevitz P. Biological membranes: the dynamics of their organization.Annu Rev Physiol. 1972; 34: 117-140Crossref PubMed Google Scholar De Broe et al.6.De Broe M.E. Wieme R.J. Logghe G.N. et al.Spontaneous shedding of plasma membrane fragments by human cells in vivo and in vitro.Clin Chim Acta. 1977; 81: 237-245Crossref PubMed Google Scholar first suggested that circular plasmamembrane fragments released from human cells may result from a specific process and showed that they may carry functional membrane enzymes in the same ratio as the membrane of the cells of origin. However, only recent studies have assigned a defined function to the vesicles/exosomes released in the microenvironment by various cell types. Two distinct processes of vesicle release from the cells have been described. MVs may derive from the endosomal membrane compartment that after fusion with the plasma membrane are extruded from the cell surface of activated cells as exosomes.7.Heijnen H.F. Schiel A.E. Fijnheer R. et al.Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules.Blood. 1999; 94: 3791-3799Crossref PubMed Google Scholar, 8.Rozmyslowicz T. Majka M. Kijowski J. et al.Platelet- and megakaryocyte-derived microparticles transfer CXCR4 receptor to CXCR4-null cells and make them susceptible to infection by X4-HIV.AIDS. 2003; 17: 33-42Crossref PubMed Scopus (129) Google Scholar Otherwise, MVs may take origin by direct budding from the cell plasma membrane as shedding vesicles.9.Cocucci E. Racchetti G. Meldolesi J. Shedding microvesicles: artefacts no more.Trends Cell Biol. 2008; 19: 43-51Abstract Full Text Full Text PDF Scopus (0) Google Scholar As the vesicle population detectable both in vitro and in vivo is a mixed population of exosomes and shedding vesicles, we will refer to them collectively as MVs. Released MVs may remain in the extracellular space in proximity of the place of origin or may enter into the biological fluids reaching distant sites. This may explain the presence of MVs in the plasma, urine, milk, and cerebrospinal fluid. The bulk of MVs present in the circulation is derived from platelets,10.George J.N. Thoi L.L. McManus L.M. et al.Isolation of human platelet membrane microparticles from plasma and serum.Blood. 1982; 60: 834-840Crossref PubMed Google Scholar and in less extent from other blood cells and endothelial cells.11.Martinez M.C. Tesse A. Zobairi F. et al.Shed membrane microparticles from circulating and vascular cells in regulating vascular function.Am J Physiol Hearth Circ Physiol. 2005; 288: H1004-H1009Crossref PubMed Scopus (0) Google Scholar The MVs derived from platelets are also designed as microparticles,10.George J.N. Thoi L.L. McManus L.M. et al.Isolation of human platelet membrane microparticles from plasma and serum.Blood. 1982; 60: 834-840Crossref PubMed Google Scholar whereas those derived from polymorphonuclear leukocytes are also named ectosomes.12.Hess C. Sadallah S. Hefti A. et al.Ectosomes released by human neutrophils are specialized functional units.J Immunol. 1999; 163: 4564-4573PubMed Google Scholar Finally, MVs released during morphogenesis of multicellular organisms are indicated as argosomes.13.Greco V. Hannus M. Eaton S. Argosomes: a potential vehicle for the spread of morphogens through epithelia.Cell. 2001; 106: 633-645Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar Besides normal cells, tumor cells may also release MVs, and in patients suffering from neoplastic diseases, tumor-derived MVs may be detected within the biological fluids.14.Kim H.K. Song K.S. Park Y.S. et al.Elevated levels of circulating platelet microparticles, VEGF, IL-6 and RANTES in patients with gastric cancer: possible role of a metastasis predictor.Eur J Cancer. 2003; 39: 184-191Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 15.Iero M. Valenti R. Huber V. et al.Tumour-released exosomes and their implications in cancer immunity.Cell Death Differ. 2008; 15: 80-88Crossref PubMed Scopus (203) Google Scholar Therefore, MVs are an assorted population, differing in cellular origin, number, size, and antigenic composition,16.Diamant M. Tushuizen M.E. Sturk A. et al.Cellular microparticles: new players in the field of vascular disease?.Eur J Clin Invest. 2004; 34: 392-401Crossref PubMed Scopus (237) Google Scholar that are shed by various cell types in physiological and pathological conditions. The release of MVs may be constitutive or consequent to cell activation by soluble agonists, by physical or chemical stress such as the oxidative stress and hypoxia, and by shear stress.4.Ratajczak J. Wysoczynski M. Hayek F. et al.Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication.Leukemia. 2006; 20: 1487-1495Crossref PubMed Scopus (443) Google ScholarExosomes have an endosome origin and are a rather homogenous population with a size ranging from 30 to 120 nm.7.Heijnen H.F. Schiel A.E. Fijnheer R. et al.Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules.Blood. 1999; 94: 3791-3799Crossref PubMed Google Scholar They are stored as intraluminal vesicles within multivesicular bodies of the late endosome and are released when these multivesicular bodies fuse with the cell membrane (Figure 1a). Our knowledge on the mechanism of assembly and sorting of the exosomes is only partial, because of the fact that a common sorting signal for all cell types has not so far been identified.17.Johnstone R.M. Exosomes biological significance: a concise review.Blood Cells Mol Dis. 2006; 36: 315-321Crossref PubMed Scopus (158) Google Scholar They are released by exocytosis through a mechanism dependent on cytoskeleton activation and under the regulation of p53 protein.18.Yu X. Harris S.L. Levine A.J. The regulation of exosome secretion: a novel function of the p53 protein.Cancer Res. 2006; 66: 4795-4801Crossref PubMed Scopus (221) Google ScholarShedding vesicles are usually larger than exosomes with size ranging from 100 nm to 1 μm. Formation of shedding vesicles takes place from the budding of small cytoplasmic protrusions followed by their detachment from the cell surface (Figure 1b). This process is dependent on calcium influx, calpain, and cytoskeleton reorganization.9.Cocucci E. Racchetti G. Meldolesi J. Shedding microvesicles: artefacts no more.Trends Cell Biol. 2008; 19: 43-51Abstract Full Text Full Text PDF Scopus (0) Google Scholar Schara et al.19.Schara K. Jansa V. Sustar V. et al.Mechanisms for the formation of membranous nanostructures in cell-to-cell communication.Cell Mol Biol Lett. 2009; 14: 636-656Crossref PubMed Scopus (22) Google Scholar describe two physical mechanisms involved in the formation of MVs and nanotubes: the curvature-mediated lateral redistribution of membrane components with the formation of membrane nanodomains and the plasma-mediated attractive forces between membranes. The intracellular levels of calcium ions modify the asymmetric phospholipid distribution of plasmamembranes by specific enzymes named flippase, floppase, and scramblase.20.Hugel B. Martinez M.C. Kunzelmann C. et al.Membrane microparticles: two sides of the coin.Physiology (Bethesda). 2005; 20: 22-27Crossref PubMed Google Scholar The increase in calcium ions inhibits translocase and induces activation of scramblase that translocates phosphatydilserine from the inner leaflet of the cell membrane bilayer to the outer. Therefore, MVs expose on their surface large amounts of phosphatydilserine and are enriched in proteins associated with membrane lipid rafts.21.Del Conde I. Shrimpton C.N. Thiagarajan P. et al.Tissue-factor-bearing microvesicles arise from lipids rafts and fuse with activated platelets to initiate coagulation.Blood. 2005; 106: 1604-1611Crossref PubMed Scopus (378) Google Scholar Moreover, the intracellular pathways that activate reorganization of cytoskeleton induce the detachment of plasmamembrane protrusions from the cortical actin. Calcium ions by activation of calpain that cleaves tallin and activin and of gelsolin that cleaves actin-capping proteins also favor the reorganization of cytoskeleton.22.Pap E. Pallinger E. Pasztoi M. et al.Highlights of a new type of intercellular communication: microvesicle-based information transfer.Inflamm Res. 2009; 58: 1-8Crossref PubMed Scopus (90) Google Scholar Therefore, depending on the cell of origin and on the mechanism of formation, MVs vary on size and molecular composition. It is now recognized that MVs are an integral part of the intercellular microenvironment and may act as regulators of cell-to-cell communication. This concept is based on the observation that MVs released from a given cell type may interact through specific receptor ligands with other cells, leading to target cell stimulation directly or by transferring surface receptors.23.Janowska-Wieczorek A. Majka M. Kijowski J. et al.Platelet-derived microparticles bind to hematopoietic progenitor cells and enhance their engraftment.Blood. 2001; 98: 3143-3149Crossref PubMed Scopus (175) Google Scholar, 24.Morel O. Toti F. Hugel B. et al.Cellular microparticles: a disseminated storage pool of bioactive vascular effectors.Curr Opin Hematol. 2004; 11: 156-164Crossref PubMed Scopus (201) Google Scholar This implicates that MVs interact only with target cells that specifically recognize rather than just with any cell present in the microenvironment.25.Lösche W. Scholz T. Temmler U. et al.Platelet-derived microvesicles transfer tissue factor to monocytes but not to neutrophils.Platelets. 2004; 15: 109-115Crossref PubMed Scopus (38) Google Scholar This interaction may either be limited to a receptor-mediated binding to the surface of target cells forming a platform for assembly of multimolecular complexes or leading to cell signaling, either to be followed by internalization as a result of direct fusion or endocytic uptake by target cells.9.Cocucci E. Racchetti G. Meldolesi J. Shedding microvesicles: artefacts no more.Trends Cell Biol. 2008; 19: 43-51Abstract Full Text Full Text PDF Scopus (0) Google Scholar Once internalized, MVs can fuse their membranes with those of endosomes, thus leading to a horizontal transfer of their content in the cytosol of target cells. Alternatively, they may remain segregated within endosomes and be transferred to lysosomes or dismissed by the cells following the fusion with the plasmamembrane, thus leading to a process of transcytosis.9.Cocucci E. Racchetti G. Meldolesi J. Shedding microvesicles: artefacts no more.Trends Cell Biol. 2008; 19: 43-51Abstract Full Text Full Text PDF Scopus (0) Google Scholar Ratajczak et al.4.Ratajczak J. Wysoczynski M. Hayek F. et al.Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication.Leukemia. 2006; 20: 1487-1495Crossref PubMed Scopus (443) Google Scholar proposed that MV-mediated cell-to-cell communication emerged very early during evolution as a template for the development of further more refined mechanisms of cell communication. MVs may influence the behavior of target cells in multiple ways (Figure 2). MVs derived from platelets, for instance, have an important role in coagulation as their phosphatydilserine-enriched membranes provide a surface for assembly of clotting factors.4.Ratajczak J. Wysoczynski M. Hayek F. et al.Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication.Leukemia. 2006; 20: 1487-1495Crossref PubMed Scopus (443) Google Scholar, 9.Cocucci E. Racchetti G. Meldolesi J. Shedding microvesicles: artefacts no more.Trends Cell Biol. 2008; 19: 43-51Abstract Full Text Full Text PDF Scopus (0) Google Scholar, 26.Zwaal R.F. Comfurius P. Bevers E.M. et al.Scott syndrome, a bleeding disorder caused by defective scrambling of membrane phospholipids.Biochim Biophys Acta. 2004; 1636: 119-128Crossref PubMed Scopus (115) Google Scholar The coagulation defects seen in Scott syndrome depend on defective scrambling of membrane phospholipids with an impaired formation of MVs.26.Zwaal R.F. Comfurius P. Bevers E.M. et al.Scott syndrome, a bleeding disorder caused by defective scrambling of membrane phospholipids.Biochim Biophys Acta. 2004; 1636: 119-128Crossref PubMed Scopus (115) Google Scholar After activation, platelets shed MVs coated with tissue factor that may interact with macrophages, neutrophils, and other platelets by ligation with molecules expressed on the surface of these cells such as P-selectin.27.Polgar J. Matuskova J. Wagner D.D. The P-selectin, tissue factor, coagulation triad.J Thromb Haemost. 2005; 3: 1590-1596Crossref PubMed Scopus (174) Google Scholar On the other hand, MVs released from neutrophils express activated leukocyte integrin alpha M beta2 (Mac-1) that is able to induce platelet activation.28.Andrews R.K. Berndt M.C. Platelet physiology and thrombosis.Thromb Res. 2004; 114: 447-453Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar Moreover, platelet-derived MVs, besides coagulation, trigger various cell responses as they activate endothelial cells,29.Barry O.P. Pratico D. Lawson J.A. et al.Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles.J Clin Invest. 1997; 99: 2118-2127Crossref PubMed Scopus (370) Google Scholar polymorphonuclear neutrophils,30.Miyamoto S. Kowalska M.A. Marcinkiewicz C. et al.Interaction of leukocytes with platelet microparticles derived from outdated platelet concentrates.Thromb Haemost. 1998; 80: 982-988PubMed Google Scholar and monocytes,31.Barry O.P. Kazanietz M.G. Praticò D. et al.Arachidonic acid in platelet microparticles up-regulates cyclooxygenase-2-dependent prostaglandin formation via a protein kinase C/mitogen-activated protein kinase-dependent pathway.J Biol Chem. 1999; 274: 7545-7556Crossref PubMed Scopus (157) Google Scholar and influence the functions of normal and malignant human hemopoietic cells.4.Ratajczak J. Wysoczynski M. Hayek F. et al.Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication.Leukemia. 2006; 20: 1487-1495Crossref PubMed Scopus (443) Google Scholar The transferring of receptors between cells is supported by the observation that bystander B cells rapidly acquire antigen receptors from activated B cells by a membrane transfer.32.Quah B.J. Barlow V.P. McPhun V. et al.Bystander B cells rapidly acquire antigen receptors from activated B cells by membrane transfer.Proc Natl Acad Sci USA. 2008; 105: 4259-4264Crossref PubMed Scopus (29) Google Scholar This allows an amplified expansion of the antigen-binding B cells with the ability to present a specific antigen to CD4 T cells. A number of other receptors were found to be transferred from one to another cell type. For instance, MVs can transfer the adhesion molecule CD41 from platelets to endothelial cells33.Barry O.P. Praticò D. Savani R.C. et al.Modulation of monocyte-endothelial cell interactions by platelet microparticles.J Clin Invest. 1998; 102: 136-144Crossref PubMed Google Scholar or to tumor cells,23.Janowska-Wieczorek A. Majka M. Kijowski J. et al.Platelet-derived microparticles bind to hematopoietic progenitor cells and enhance their engraftment.Blood. 2001; 98: 3143-3149Crossref PubMed Scopus (175) Google Scholar conferring pro-adhesive properties to them. MV-mediated transfer of Fas ligand from tumor cells induces apoptosis of activated T cells favoring tumor immune escape.34.Kim J.W. Wieckowski E. Taylor D.D. et al.Fas ligand-positive membranous vesicles isolated from sera of patients with oral cancer induce apoptosis of activated T lymphocytes.Clin Cancer Res. 2005; 11: 1010-1020PubMed Google Scholar On the other hand, formation of shedding vesicles may be protective for cells that dismiss from their membranes to the extracellular compartment the potentially harmful molecules such as Fas or the membrane attack complex.35.Camussi G. Salvidio G. Biesecker G. et al.Heymann antibodies induce complement-dependent injury of rat glomerular visceral epithelial cells.J Immunol. 1987; 139: 2906-2914PubMed Google Scholar, 36.Pilzer D. Fishelson Z. Mortalin/GRP75 promotes release of membrane vesicles from immune attacked cells and protection from complement-mediated lysis.Int Immunol. 2005; 17: 1239-1248Crossref PubMed Scopus (51) Google Scholar It has also been postulated that MVs may contribute in spreading certain infective agents such as human immunodeficiency virus type 1.37.Fackler O.T. Peterlin B.M. Endocytic entry of HIV-1.Curr Biol. 2000; 10: 1005-1008Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 38.Février B. Raposo G. Exosomes: endosomal-derived vesicles shipping extracellular messages.Curr Opin Cell Biol. 2004; 16: 415-421Crossref PubMed Scopus (456) Google Scholar Indeed, the transfer by MVs of CXCR4 (chemokine (CXC motif) receptor 4) and CCR5 (chemokine (CC motif) receptor 5) chemokine co-receptors for human immunodeficiency virus type I may favor the entry of the virus in cells other than the lympho-hemopoietic lineage.8.Rozmyslowicz T. Majka M. Kijowski J. et al.Platelet- and megakaryocyte-derived microparticles transfer CXCR4 receptor to CXCR4-null cells and make them susceptible to infection by X4-HIV.AIDS. 2003; 17: 33-42Crossref PubMed Scopus (129) Google Scholar, 39.Mack M. Kleinschmidt A. Brühl H. et al.Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodeficiency virus 1 infection.Nat Med. 2000; 6: 769-775Crossref PubMed Scopus (253) Google Scholar However, the viral transfer by MVs may also occur by the so-called ‘Trojan exosome hypothesis’ involving a direct delivery.40.Gould S.J. Booth A.M. Hildreth J.E. The Trojan exosome hypothesis.Proc Natl Acad Sci USA. 2003; 100: 10592-10597Crossref PubMed Scopus (253) Google Scholar An example of this mechanism is the recently reported MV-mediated transfer of a cell death message via encapsulated caspase-1.41.Sarkar A. Mitra S. Mehta S. et al.Monocyte derived microvesicles deliver a cell death message via encapsulated caspase-1.PLoS One. 2009; 4: e7140Crossref PubMed Scopus (26) Google Scholar It has been found that endotoxin-stimulated monocytes induce the cell death of vascular smooth muscle cells by releasing MVs containing caspase-1. This trans-cellular apoptosis induction pathway depends on the function of the delivered caspase-1 within the target cells. It has also been suggested that MVs may contribute to dissemination of certain infective agents, such as human immunodeficiency virus or prions.42.Facler O.T. Peterlin B.M. Endocytic entry of HIV-1.Curr Biol. 2000; 10: 1005-1008Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 43.Fevrier B. Vilette D. Archer F. et al.Cells release prions in association with exosomes.Proc Natl Acad Sci USA. 2004; 101: 9683-9688Crossref PubMed Scopus (406) Google Scholar The occurrence of epigenetic changes has been frequently reported in co-culture conditions. An explanation of this phenomenon is the transfer of genetic information between cells. It has been shown that tumor-derived MVs may transfer not only surface determinants but also mRNA of tumor cells to monocytes.44.Baj-Krzyworzeka M. Szatanek R. Weglarczyk K. et al.Tumour-derived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes.Cancer Immunol Immunother. 2006; 55: 808-818Crossref PubMed Scopus (169) Google Scholar Ratajczak et al.45.Ratajczak J. Miekus K. Kucia M. et al.Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery.Leukemia. 2006; 20: 847-856Crossref PubMed Scopus (392) Google Scholar demonstrated that MVs derived from murine embryonic stem cells (ESCs) may induce an epigenetic reprogramming of target cells. ES-derived MVs were shown to improve survival of hematopoietic stem/progenitor cells, to induce upregulation of early pluripotent and early hematopoietic markers, and to induce phosphorylation of mitogen-activated protein kinase p42/44 and Akt. In addition, ES-derived MVs were shown to express mRNAs for several pluripotent transcription factors that can be delivered to target cells and translated to the corresponding proteins. As RNase inhibited MV-mediated biological effect, the involvement of mRNA in the observed biological effects was suggested.45.Ratajczak J. Miekus K. Kucia M. et al.Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery.Leukemia. 2006; 20: 847-856Crossref PubMed Scopus (392) Google Scholar We demonstrated that MVs derived from human endothelial progenitor cells can also act as a vehicle for mRNA transport among cells.46.Deregibus M.C. Cantaluppi V. Calogero R. et al.Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA.Blood. 2007; 110: 2440-2448Crossref PubMed Scopus (336) Google Scholar MVs generated from endothelial progenitor cells were incorporated in normal endothelial cells by interaction with α4 and β1 integrins expressed on their surface and activated an angiogenic program.46.Deregibus M.C. Cantaluppi V. Calogero R. et al.Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA.Blood. 2007; 110: 2440-2448Crossref PubMed Scopus (336) Google Scholar This effect was also proved in vivo in severe combined immunodeficient mice, where MV-stimulated human endothelial cells subcutaneously implanted within Matrigel organized in a patent vessel network connected with the murine vasculature. RNase pretreatment of MVs abrogated their angiogenic activity even though they were internalized by endothelial cells, suggesting a critical role for RNA transfer following MV incorporation. The molecular analysis of mRNA indicated that MVs derived from endothelial progenitor cells were shuttling a specific subset of cellular mRNA, including mRNA associated with pathways relevant for angiogenesis such as the PI3K/AKT and endothelial nitric oxide synthase signaling pathways. Protein expression and functional studies demonstrated that phosphatidylinositol 3-kinase and endothelial nitric oxide synthase were upregulated in target cells after MV incorporation. As a proof of transduction in target cells of mRNA delivered from MVs, we used the green fluorescent protein (GFP) mRNA as reporter. Endothelial cells targeted with MVs carrying GFP mRNA produced the GFP proteins.46.Deregibus M.C. Cantaluppi V. Calogero R. et al.Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA.Blood. 2007; 110: 2440-2448Crossref PubMed Scopus (336) Google Scholar More recently, we demonstrated that MVs derived from human stem cells may also deliver in vivo human mRNA to mouse cells, resulting in protein translation.47.Bruno S. Grange C. Deregibus M.C. et al.Mesenchymal stem cell-derived microvesicles protect against acute tubular injury.J Am Soc Nephrol. 2009; 20: 1053-1067Crossref PubMed Scopus (268) Google Scholar, 48.Herrera M.B. Fonsato V. Gatti S. et al.Human liver stem cell-derived microvesicles accelerate hepatic regeneration in hepatectomized rats.J Cell Mol Med. 2010; 14: 1605-1618Crossref PubMed Scopus (79) Google Scholar Yuan et al.49.Yuan A. Farber E.L. Rapoport A.L. et al.Transfer of microRNAs by embryonic stem cell microvesicles.PLoS One. 2009; 4: e4722Crossref PubMed Scopus (176) Google Scholar have recently shown that besides mRNA, MVs may transfer in target cells microRNA. They demonstrated that MVs derived from ESCs contain abundant microRNA and that they can transfer a subset of microRNAs to mouse embryonic fibroblasts in vitro. As microRNAs are naturally occurring regulators of protein translation, this observation opens the possibility that stem cells can alter the expression of genes in neighboring cells by transferring microRNAs contained in MVs. Inflammation is sustained by multiple interactions among cells. In this context, MVs may act at different stages of the process by carrying either anti-inflammatory or pro-inflammatory factors.50.Ardoin S.P. Shanahan J.C. Pisetsky D.S. The role of microparticles in inflammation and thrombosis.Scand J Immunol. 2007; 66: 159-165Crossref PubMed Scopus (100) Google Scholar MVs derived from platelets and macrophages were found to be accumulated in the lipid core of the atherosclerotic plaques with the potential of triggering pro-inflammatory, angiogenic, and thrombotic signals.51.Leroyer A.S. Tedgui A. Boulanger C.M. Role of microparticles in atherothrombosis.J Intern Med. 2008; 263: 528-537Crossref PubMed Scopus (72) Google Scholar These observations rise the possibility that targeting MVs may be a therapeutic strategy in atherosclerosis.9.Cocucci E. Racchetti G. Meldolesi J. Shedding microvesicles: artefacts no more.Trends Cell Biol. 2008; 19: 43-51Abstract Full Text Full Text PDF Scopus (0) Google Scholar, 50.Ardoin S.P. Shanahan J.C. Pisetsky D.S. The role of microparticles in inflammation and thrombosis.Scand J Immunol. 2007; 66: 159-165Crossref PubMed Scopus (100) Google Scholar Indeed, increased levels of MVs of mainly endothelial origin were observed in cardiovascular pathology.52.Simak J. Gelderman M.P. Cell membrane microparticles in blood and blood products: potentially pathogenic agents and diagnostic markers.Transfus Med Rev. 2006; 20: 1-26Abstract Ful
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