Microvesicles

Microvesicles (sometimes called, circulating microvesicles, or microparticles.) are fragments of plasma membrane ranging from 100 nm to 1000 nm shed from almost all cell types. Not to be confused with smaller intracellularly generated extracellular vesicles known as exosomes. Microvesicles play a role in intercellular communication and can transport mRNA, miRNA, and proteins between cells.[1] 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.[2][3][4][5] 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

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.[6]

Endothelial microparticle

Endothelial microparticles are small vesicles that are released from endothelial cells and can be found circulating in the blood.[7]

The microparticle consists of a plasma membrane surrounding a small amount of cytosol. The membrane of the endothelial microparticle contains receptors and other cell surface molecules which enable the identification of the endothelial origin of the microparticle, and allow it to be distinguished from microparticles from other cells, such as platelets.

Although circulating endothelial microparticles can be found in the blood of normal individuals, increased numbers of circulating endothelial microparticles have been identified in individuals with certain diseases, including hypertension and cardiovascular disorders,[8] and pre-eclampsia [9] and various forms of vasculitis. The endothelial microparticles in some of these disease states have been shown to have arrays of cell surface molecules reflecting a state of endothelial dysfunction. Therefore, endothelial microparticles may be useful as an indicator or index of the functional state of the endothelium in disease, and may potentially play key roles in the pathogenesis of certain diseases, including rheumatoid arthritis.[10]

Mechanism of shedding

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.[11]

Microvesicles and cancer

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.[12][13]

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 important 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 potential markers for tumor diagnostics.[14]

Microvesicles and intercellular communication

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.[1][15] 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.[16]

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.[17]

Microvesicles and Rheumatoid arthritis

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.

See also

References

  1. 1 2 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 3040683Freely accessible. PMID 21285958.
  2. ↑ 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.
  3. ↑ 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). Lo, Yuk Ming Dennis, ed. "Detection of microRNA Expression in Human Peripheral Blood Microvesicles". PLoS ONE. 3 (11): e3694. Bibcode:2008PLoSO...3.3694H. doi:10.1371/journal.pone.0003694. PMC 2577891Freely accessible. PMID 19002258.
  4. ↑ 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 2829939Freely accessible. PMID 20079801.
  5. ↑ 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.
  6. ↑ 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
  7. ↑ Davizon, Pavela; López, José (September 2009). "Microparticles and thrombotic disease.". Current Opinion in Hematology. 16 (5): 334–341. doi:10.1097/MOH.0b013e32832ea49c. PMID 19606028.
  8. ↑ Boulanger, Chantal M (March 2010). "Microparticles, vascular function and hypertension.". Current Opinion in Nephrology and Hypertension. 19 (2): 177–180. doi:10.1097/MNH.0b013e32833640fd.
  9. ↑ Ling L (Feb 2014). "Evaluation of plasma endothelial microparticles in pre-eclampsia." (PDF). J Int Med Res. 42 (1): 42–51. doi:10.1177/0300060513504362. PMID 24319051.
  10. ↑ Boilard, E.; et al. (January 2010). "Platelets Amplify Inflammation in Arthritis via Collagen-Dependent Microparticle Production". Science. 327 (5965): 580–583. doi:10.1126/science.1181928. PMC 2927861Freely accessible. PMID 20110505.
  11. ↑ 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.
  12. ↑ Microvesicles (MVS) Derived From Adult Stem Cells For Use In The Therapeutic Treatment of a Tumor Disease. PCT/EP2011/052945 Available online
  13. ↑ 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
  14. ↑ 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. Available online
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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" (PDF). Molecular & Cellular Proteomics. 9 (6): 1085–99. doi:10.1074/mcp.M900381-MCP200. PMC 2877972Freely accessible. PMID 20124223.

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