Microvesicles

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Microvesicles (sometimes called exosomes, circulating microvesicles, or microparticles)[1] are fragments of plasma membrane ranging from 50 nm to 1000 nm shed from almost all cell types. Microvesicles play a role in intercellular communication and can transport mRNA, miRNA, and proteins between cells.[2] Microvesicles have been implicated in the process of a remarkable anti-tumor reversal effect in cancer, tumor immune suppression, metastasis, tumor-stroma interactions and angiogenesis along with having a primary role in tissue regeneration.[3][4][5][6] They originate directly from the plasma membrane of the cell and reflect the antigenic content of the cells from which they originate. They remove misfolded proteins, cytotoxic agents and metabolic waste from the cell.

Microvesicle sources[edit]

Different cells can release microvesicles from the plasma membrane. Sources of microvesicles include megakaryocytes, blood platelets, monocytes, neutrophils, tumor cells and placenta.

Platelets play an important role in maintaining hemostasis: they promote thrombus growth, and thus they prevent loss of blood. Moreover they enhance immune response, since they express the molecule CD154 (CD40L). Platelets are activated by inflammation, infection, or injury, and after their activation microvesicles containing CD154 are released from platelets. CD154 is a crucial molecule in the development of T cell-dependent humoral immune response. CD154 knockout mice are incapable of producing IgG, IgE, or IgA as a response to antigens. Microvesicles can also transfer prions and molecules CD41 and CXCR4.[7]

Mechanism of shedding[edit]

There are three mechanisms which lead to release of vesicles into the extracellular space. First of these mechanisms is exocytosis from multivesicular bodies and the formation of exosomes. Another mechanism is budding of microvesicles directly from a plasma membrane. And the last one is cell death leading to the blebbing of apoptotic bodies. These are all energy-requiring processes.

Under physiologic conditions, the plasma membrane of cells has an asymmetric distribution of phospholipids. Aminophospholipids, phosphatidylserine, and phosphatidylethanolamine are specifically sequestered in the inner leaflet of the membrane. The transbilayer lipid distribution is under the control of three phospholipidic pumps: an inward-directed pump, or flippase; an outward-directed pump, or floppase; and a lipid scramblase, responsible for non-specific redistribution of lipids across the membrane.

After cell stimulation, including apoptosis, a subsequent cytosolic Ca2+ increase promotes the loss of phospholipid asymmetry of the plasma membrane, subsequent phosphatidylserine exposure, and a transient phospholipidic imbalance between the external leaflet at the expense of the inner leaflet, leading to budding of the plasma membrane and microvesicle release.[8]

Microvesicles and cancer[edit]

Evidence produced by independent research groups has demonstrated that microvesicles from the cells of healthy tissues, or selected miRNAs from these microvesicles, can be employed to reverse many tumors in pre-clinical cancer models, and may be used in combination with chemotherapy.[9][10]

Conversely, microvesicles processed from a tumor cell are involved in the transport of cancer proteins and in delivering microRNA to the surrounding healthy tissue. It leads to a change of healthy cell phenotype and creates a tumor-friendly environment. Microvesicles play an importmant role in tumor angiogenesis and in the degradation of matrix due to the presence of metalloproteases, which facilitate metastasis. They are also involved in intensification of the function of regulatory T-lymphocytes and in the induction of apoptosis of cytotoxic T-lymphocytes, because microvesicles released from a tumor cell contain Fas ligand and TRAIL. They prevent differentiation of monocytes to dendritic cells.

Tumor microvesicles also carry tumor antigen, so they can be an instrument for developing tumor vaccines. Circulating miRNA and segments of DNA in all body fluids can be potencial markers for tumor diagnostics.[11]

Microvesicles and intercellular communication[edit]

Scientists are actively researching the role that exosomes may play in cell-to-cell signaling, hypothesizing that because exosomes can merge with and release their contents into cells that are distant from their cell of origin (see membrane vesicle trafficking), they may influence processes in the recipient cell. For example, RNA that is shuttled from one cell to another, known as "exosomal shuttle RNA," could potentially affect protein production in the recipient cell.[2][12] By transferring molecules from one cell to another, exosomes from certain cells of the immune system, such as dendritic cells and B cells, may play a functional role in mediating adaptive immune responses to pathogens and tumors.[13]

Conversely, exosome production and content may be influenced by molecular signals received by the cell of origin. As evidence for this hypothesis, tumor cells exposed to hypoxia secrete exosomes with enhanced angiogenic and metastatic potential, suggesting that tumor cells adapt to a hypoxic microenvironment by secreting exosomes to stimulate angiogenesis or facilitate metastasis to more favorable environment.[14]

Currently, there are no proven mechanisms by which microvesicles trigger intercellular communication. Possible mechanisms by which microvesicles trigger intercellular communication are paracrine, fusion with cells, and phagocytosis. [15]

Microvesicles and Rheumatoid arthritis[edit]

Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by inflammation of joints. In the early stage there are abundant Th17 cells producing proinflammatory cytokines IL-17A, IL-17F, TNF, IL-21, and IL-22 in the synovial fluid. regulatory T-lymphocytes have a limited capability to control these cells. In the late stage, the extent of inflammation correlates with numbers of activated macrophages that contribute to joint inflammation and bone and cartilage destruction, because they have the ability to transform themselves into osteoclasts that destroy bone tissue. Synthesis of reactive oxygen species, proteases, and prostaglandins by neutrophils is increased. Activation of platelets via collagen receptor GPVI stimulates the release of microvesicles from platelet cytoplasmic membranes. These microparticles are detectable at a high level in synovial fluid, and they promote joint inflammation by transporting proinflammatory cytokine IL-1.

Terminology[edit]

Microvesicles are also referred to as exosomes, epididimosomes, argosomes, exosome-like vesicles, microparticles, promininosomes, prostasomes, dexosomes, texosomes, dex, tex, archeosomes and oncosomes.[1] This confusion in terminology has led to typical exosome preparations sometimes being referred to as microvesicles and vice versa.

References[edit]

  1. ^ a b Simpson, RJ; Mathivanan, S (2012). "Extracellular Microvesicles: The Need for Internationally Recognised Nomenclature and Stringent Purification Criteria". J Proteomics Bioinform (2). doi:10.4172/jpb.10000e10. 
  2. ^ a b Balaj, L.; Lessard, R.; Dai, L.; Cho, Y. J.; Pomeroy, S. L.; Breakefield, X. O.; Skog, J. (2011). "Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences". Nature Communications 2 (2): 180. Bibcode:2011NatCo...2E.180B. doi:10.1038/ncomms1180. PMC 3040683. PMID 21285958.  edit
  3. ^ Ratajczak, J.; Miekus, K.; Kucia, M.; Zhang, J.; Reca, R.; Dvorak, P.; Ratajczak, M. Z. (2006). "Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery". Leukemia 20 (5): 847–856. doi:10.1038/sj.leu.2404132. PMID 16453000.  edit
  4. ^ Hunter, M.; Ismail, N.; Zhang, X.; Aguda, B.; Lee, E.; Yu, L.; Xiao, T.; Schafer, J.; Lee, M.; Schmittgen, T. D.; Nana-Sinkam, S. P.; Jarjoura, D.; Marsh, C. B. (2008). "Detection of microRNA Expression in Human Peripheral Blood Microvesicles". In Lo, Yuk Ming Dennis. PLoS ONE 3 (11): e3694. Bibcode:2008PLoSO...3.3694H. doi:10.1371/journal.pone.0003694. PMC 2577891. PMID 19002258.  edit
  5. ^ Aliotta, J.; Pereira, M.; Johnson, K.; De Paz, N.; Dooner, M.; Puente, N.; Ayala, C.; Brilliant, K.; Berz, D.; Lee, D.; Ramratnam, B.; McMillan, P. N.; Hixson, D. C.; Josic, D.; Quesenberry, P. J. (2010). "Microvesicle entry into marrow cells mediates tissue-specific changes in mRNA by direct delivery of mRNA and induction of transcription". Experimental hematology 38 (3): 233–245. doi:10.1016/j.exphem.2010.01.002. PMC 2829939. PMID 20079801.  edit
  6. ^ Castellana, D.; Zobairi, F.; Martinez, M. C.; Panaro, M. A.; Mitolo, V.; Freyssinet, J. -M.; Kunzelmann, C. (2009). "Membrane Microvesicles as Actors in the Establishment of a Favorable Prostatic Tumoral Niche: A Role for Activated Fibroblasts and CX3CL1-CX3CR1 Axis". Cancer Research 69 (3): 785–793. doi:10.1158/0008-5472.CAN-08-1946. PMID 19155311.  edit
  7. ^ Sprague, D. L. ;Elzey, B. D. ;Crist, S. A. ;Waldschmidt, T. J. ;Jensen, R. J. ;Ratliff, T. L. Platelet-mediated modulation of adaptive immunity: unique delivery of CD154 signal by platelet-derived membrane vesicles. (2008). Blood. 111(10):5028-36. Available online
  8. ^ Hugel, B.; Martinez, M. C.; Kunzelmann, C.; Freyssinet, J. -M. (2005). "Membrane Microparticles: Two Sides of the Coin". Physiology 20: 22–27. doi:10.1152/physiol.00029.2004. PMID 15653836.  edit
  9. ^ Microvesicles (MVS) Derived From Adult Stem Cells For Use In The Therapeutic Treatment of a Tumor Disease. PCT/EP2011/052945 Available online
  10. ^ Human Liver Stem Cell-Derived Microvesicles Inhibit Hepatoma Growth in SCID Mice by Delivering Antitumor MicroRNAs. Camussi et al; STEM CELLS [2012,30]Available online
  11. ^ Muralidharan-Chari, V. ;Clancy, J. W. ;Sedgwick, A. ;D'Souza-Schorey, C. Microvesicles: mediators of extracellular communication during cancer progression. (2010). J Cell Sci. 123(Pt10):1603-11. Avalaible online
  12. ^ Valadi, H, Ekström, K, Bossios, A, Sjöstrand, M, Lee, JJ, Lötvall, JO (2007). "Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells". Nat. Cell Biol. 9 (6): 654–9. doi:10.1038/ncb1596. PMID 17486113. 
  13. ^ Li XB, Zhang ZR, Schluesener HJ, Xu SQ (2006). "Role of exosomes in immune regulation". J. Cell. Mol. Med. 10 (2): 364–75. doi:10.1111/j.1582-4934.2006.tb00405.x. PMID 16796805. 
  14. ^ Park, J.E.; Tan, H.S.; Datta, A.; Lai, R.C.; Zhang, H.; Meng, W.; Lim, S.-K.; Sze, S.K. (2010). "Hypoxic Tumor Cell Modulates Its Microenvironment to Enhance Angiogenic and Metastatic Potential by Secretion of Proteins and Exosomes". Molecular and Cellular Proteomics 9 (6): 1085–99. doi:10.1074/mcp.M900381-MCP200. PMC 2877972. PMID 20124223. 
  15. ^ Mathivanan, S. Exosomes and Shedding Microvesicles are Mediators of Intercellular Communication: How do they Communicate with the Target Cells? (2012). J Biotechnol Biomater 2012, 2:6. Avalaible online

See also[edit]

International Society for Extracellular Vesicles, Exocytosis, Membrane vesicle trafficking.

External links[edit]