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Microvesicles (sometimes called, circulating microvesicles, or microparticles) are a type of extracellular vesicle (EV).[1] Microvesicles are circular fragments of plasma membrane[2] 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.[3] 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.[4][5][6][7] 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.[8]

Endothelial microparticle[edit]

Endothelial microparticles are small vesicles that are released from endothelial cells and can be found circulating in the blood.[9]

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,[10] and pre-eclampsia [11] 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.[12]

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.[13]

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.[14][15]

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.[16]

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.[3][17] 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.[18]

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.[19]

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.

See also[edit]


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