Microvesicles

Microvesicles (sometimes called exosomes, circulating microvesicles, or microparticles) 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. 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. 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 an immune response since platelets express the molecule CD154 (CD40L). There are a few stimules activating platelets including inflammation, infection or injury and after their activation microvesicles containing CD154 are released from platelets. CD154 is a crucial molecule in development of T-cell dependent humoral immune response. Knockout mice in the gene for CD154 are incapable to produce IgG, IgE, IgA as a response to antigens. Microvesicles can also transfer prions and molecules CD41 and CXCR4.

Mechanism of shedding

There are three mechanisms which lead to cell components release 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 cytoplasmatic membrane and the last one is cell death leading to the formation 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 microvesicles release.

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.

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 creating tumor environment. They 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 from differentation of monocytes to dendritic cells. On the other hand microvesicles carry tumor antigen so they can be an instrument for developing tumor vaccinnes. Circulating miRNA and segments of DNA in all body fluids can be potencial markers for tumor diagnostics. For some reason the author(s) have omitted to mention the potential therapeutic role for microvesicles in the treatment of a tumor disease. I therefore think it's important to put this in, as otherwise readers may think that MV = Cancer - that may be true for MVs released from tumor (cancer) cells, but the evidence is quite the reverse in terms of MVs that are not ferried from cancerous cells.

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, 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. 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. 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. On the other hand, myc-immortalization of mesenchymal stem cell (MSC) did not alter the cardioprotective potency of its secreted exosomes. Currently, there are no proven mechanisms by which microvesicles trigger intercellular communication. Possible mechanisms by which microvesicles trigger intercellular communication are paracrine, fusion and phagocytosis.

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 cytokine IL-17A, IL-17F, TNF, IL-21,IL-22 in the synovial fluid and on the other hand regulatory T-lymphocytes have a limited capability. In the late stage the extent of inflammation correlates with numbers of activated macrophages that considerably contribute to joint inflammation and bone and cartilages destruction because they have the ability to transform themselves into osteoclasts destructing 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 microparticules from platelet cytoplasmic membrane. These microparticles are detectable at a high level in synovial fluid and they promote joint inflammation by transporting proinflammatory cytokine IL-1. There are also other ways how platelets contribute to the development of arthritis and it happens in a microparticle-independent manner. Platelets express Cyclooxygenase 1. Activated platelets promote phospholipase A2 activation which releases arachidonic acid from membrane phospholipids. Arachidonic acid is processed by Cyclooxygenase 1 and prostanoid precursor PGH2 is created. Prostanoid precursor PGH2 diffuses from platelets to neighbouring synovium fibroblast expressing prostacyclin synthase which results in the formation of proinflammatory prostacyclin PGI2. In rheumatoid arthritis pacient joints with elevated level of prostacyclin PGI2 was found.

Terminology

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

External links

• http://www.microvesicles.org Vesiclepedia—A database of molecules identified in extracellular vesicles.
• http://www.exocarta.org ExoCarta—A database of molecules identified in exosomes.
• Microvesicles in Purified HIV-1 Preparations
• Exosome.com