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      Extracellular Vesicles: Potential Roles in Regenerative Medicine

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          Abstract

          Extracellular vesicles (EV) consist of exosomes, which are released upon fusion of the multivesicular body with the cell membrane, and microvesicles, which are released directly from the cell membrane. EV can mediate cell–cell communication and are involved in many processes, including immune signaling, angiogenesis, stress response, senescence, proliferation, and cell differentiation. The vast amount of processes that EV are involved in and the versatility of manner in which they can influence the behavior of recipient cells make EV an interesting source for both therapeutic and diagnostic applications. Successes in the fields of tumor biology and immunology sparked the exploration of the potential of EV in the field of regenerative medicine. Indeed, EV are involved in restoring tissue and organ damage, and may partially explain the paracrine effects observed in stem cell-based therapeutic approaches. The function and content of EV may also harbor information that can be used in tissue engineering, in which paracrine signaling is employed to modulate cell recruitment, differentiation, and proliferation. In this review, we discuss the function and role of EV in regenerative medicine and elaborate on potential applications in tissue engineering.

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          Most cited references98

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          Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication.

          Normal and malignant cells shed from their surface membranes as well as secrete from the endosomal membrane compartment circular membrane fragments called microvesicles (MV). MV that are released from viable cells are usually smaller in size compared to the apoptotic bodies derived from damaged cells and unlike them do not contain fragmented DNA. Growing experimental evidence indicates that MV are an underappreciated component of the cell environment and play an important pleiotropic role in many biological processes. Generally, MV are enriched in various bioactive molecules and may (i) directly stimulate cells as a kind of 'signaling complex', (ii) transfer membrane receptors, proteins, mRNA and organelles (e.g., mitochondria) between cells and finally (iii) deliver infectious agents into cells (e.g., human immuno deficiency virus, prions). In this review, we discuss the pleiotropic effects of MV that are important for communication between cells, as well as the role of MV in carcinogenesis, coagulation, immune responses and modulation of susceptibility/infectability of cells to retroviruses or prions.
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            Exosome secretion: molecular mechanisms and roles in immune responses.

            Exosomes are small membrane vesicles, secreted by most cell types from multivesicular endosomes, and thought to play important roles in intercellular communications. Initially described in 1983, as specifically secreted by reticulocytes, exosomes became of interest for immunologists in 1996, when they were proposed to play a role in antigen presentation. More recently, the finding that exosomes carry genetic materials, mRNA and miRNA, has been a major breakthrough in the field, unveiling their capacity to vehicle genetic messages. It is now clear that not only immune cells but probably all cell types are able to secrete exosomes: their range of possible functions expands well beyond immunology to neurobiology, stem cell and tumor biology, and their use in clinical applications as biomarkers or as therapeutic tools is an extensive area of research. Despite intensive efforts to understand their functions, two issues remain to be solved in the future: (i) what are the physiological function(s) of exosomes in vivo and (ii) what are the relative contributions of exosomes and of other secreted membrane vesicles in these proposed functions? Here, we will focus on the current ideas on exosomes and immune responses, but also on their mechanisms of secretion and the use of this knowledge to elucidate the latter issue. © 2011 John Wiley & Sons A/S.
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              Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes.

              Association of major histocompatibility complex (MHC) class II molecules with peptides occurs in a series of endocytic vacuoles, termed MHC class II-enriched compartments (MIICs). Morphological criteria have defined several types of MIICs, including multivesicular MIICs, which are composed of 50-60-nm vesicles surrounded by a limiting membrane. Multivesicular MIICs can fuse with the plasma membrane, thereby releasing their internal vesicles into the extracellular space. The externalized vesicles, termed exosomes, carry MHC class II and can stimulate T-cells in vitro. In this study, we show that exosomes are enriched in the co-stimulatory molecule CD86 and in several tetraspan proteins, including CD37, CD53, CD63, CD81, and CD82. Interestingly, subcellular localization of these molecules revealed that they were concentrated on the internal membranes of multivesicular MIICs. In contrast to the tetraspans, other membrane proteins of MIICs, such as HLA-DM, Lamp-1, and Lamp-2, were mainly localized to the limiting membrane and were hardly detectable on the internal membranes of MIICs nor on exosomes. Because internal vesicles of multivesicular MIICs are thought to originate from inward budding of the limiting membrane, the differential distribution of membrane proteins on the internal and limiting membranes of MIICs has to be driven by active protein sorting.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/184365
                URI : http://frontiersin.org/people/u/142951
                URI : http://frontiersin.org/people/u/95986
                URI : http://frontiersin.org/people/u/194209
                URI : http://frontiersin.org/people/u/195157
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                03 December 2014
                2014
                : 5
                : 608
                Affiliations
                [1] 1Department of Nephrology and Hypertension, University Medical Center Utrecht , Utrecht, Netherlands
                [2] 2Department of Biomedical Engineering, Eindhoven University of Technology , Eindhoven, Netherlands
                [3] 3Department of Clinical Chemistry and Hematology, University Medical Center Utrecht , Utrecht, Netherlands
                Author notes

                Edited by: Marcella Franquesa, Erasmus Medisch Centrum, Netherlands

                Reviewed by: Rae Ritchie, Bioscience Vaccines Inc., USA; Miroslaw Kornek, University of Saarland, Germany

                *Correspondence: Bas W. M. Van Balkom, Department of Nephrology and Hypertension, UMC Utrecht, Heidelberglaan 100, G.02.402, Utrecht 3584 CX, Netherlands e-mail: b.w.m.vanbalkom@ 123456umcutrecht.nl

                This article was submitted to Immunotherapies and Vaccines, a section of the journal Frontiers in Immunology.

                Article
                10.3389/fimmu.2014.00608
                4253973
                25520717
                4337780a-82cf-491f-9197-02a41389286f
                Copyright © 2014 De Jong, Van Balkom, Schiffelers, Bouten and Verhaar.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 September 2014
                : 12 November 2014
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 142, Pages: 13, Words: 11039
                Categories
                Immunology
                Review Article

                Immunology
                regenerative medicine,tissue engineering,extracellular vesicles,exosomes,microvesicles
                Immunology
                regenerative medicine, tissue engineering, extracellular vesicles, exosomes, microvesicles

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