Microvesicle

Microvesicles are a type of extracellular vesicle that are released from the cell membrane. In multicellular organisms, microvesicles and other EVs are found both in tissues and in many types of body fluids. Delimited by a phospholipid bilayer, microvesicles can be as small as the smallest EVs or as large as 1000 nm. They are considered to be larger, on average, than intracellularly-generated EVs known as exosomes. Microvesicles play a role in intercellular communication and can transport molecules such as mRNA, miRNA, and proteins between cells.
Though initially dismissed as cellular debris, microvesicles may reflect the antigenic content of the cell of origin and have a role in cell signaling. Like other EVs, they have been implicated in numerous physiologic processes, including anti-tumor effects, tumor immune suppression, metastasis, tumor-stroma interactions, angiogenesis, and tissue regeneration. Microvesicles may also remove misfolded proteins, cytotoxic agents and metabolic waste from the cell. Changes in microvesicle levels may indicate diseases including cancer.

Formation and contents

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. 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.

Endothelial microparticles

Endothelial microparticles are small vesicles that are released from endothelial cells and can be found circulating in the blood.
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,
and pre-eclampsia 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.
Endothelial microparticles have been found to prevent apoptosis in recipient cells by inhibiting the p38 pathway via inactivating . Uptake of endothelial micoparticles is Annexin I/Phosphatidylserine receptor dependant.
Microparticles are derived from many other cell types.

Process of formation

Microvesicles and exosomes are formed and released by two slightly different mechanisms. These processes result in the release of intercellular signaling vesicles. Microvesicles are small, plasma membrane-derived particles that are released into the extracellular environment by the outward budding and fission of the plasma membrane. This budding process involves multiple signaling pathways including the elevation of intracellular calcium and reorganization of the cell's structural scaffolding. The formation and release of microvesicles involve contractile machinery that draws opposing membranes together before pinching off the membrane connection and launching the vesicle into the extracellular space.
Microvesicle budding takes place at unique locations on the cell membrane that are enriched with specific lipids and proteins reflecting their cellular origin. At these locations, proteins, lipids, and nucleic acids are selectively incorporated into microvesicles and released into the surrounding environment.
Exosomes are membrane-covered vesicles, formed intracellularly are considered to be smaller than 100 nm. In contrast to microvesicles, which are formed through a process of membrane budding, or exocytosis, exosomes are initially formed by endocytosis. Exosomes are formed by invagination within a cell to create an intracellular vesicle called an endosome, or an endocytic vesicle. In general, exosomes are formed by segregating the cargo within the endosome. Once formed, the endosome combines with a structure known as a multivesicular body. The MVB containing segregated endosomes ultimately fuses with the plasma membrane, resulting in exocytosis of the exosomes.
Once formed, both microvesicles and exosomes circulate in the extracellular space near the site of release, where they can be taken up by other cells or gradually deteriorate. In addition, some vesicles migrate significant distances by diffusion, ultimately appearing in biological fluids such as cerebrospinal fluid, blood, and urine.

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 apoptotic blebbing. 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.

Molecular contents

The lipid and protein content of microvesicles has been analyzed using various biochemical techniques. Microvesicles display a spectrum of enclosed molecules enclosed within the vesicles and their plasma membranes. Both the membrane molecular pattern and the internal contents of the vesicle depend on the cellular origin and the molecular processes triggering their formation. Because microvesicles are not intact cells, they do not contain mitochondria, Golgi, endoplasmic reticulum, or a nucleus with its associated DNA.
Microvesicle membranes consist mainly of membrane lipids and membrane proteins. Regardless of their cell type of origin, nearly all microvesicles contain proteins involved in membrane transport and fusion. They are surrounded by a phospholipid bilayer composed of several different lipid molecules. The protein content of each microvesicle reflects the origin of the cell from which it was released. For example, those released from antigen-presenting cells, such as B cells and dendritic cells, are enriched in proteins necessary for adaptive immunity, while microvesicles released from tumors contain proapoptotic molecules and oncogenic receptors.
In addition to the proteins specific to the cell type of origin, some proteins are common to most microvesicles. For example, nearly all contain the cytoplasmic proteins tubulin, actin and actin-binding proteins, as well as many proteins involved in signal transduction, cell structure and motility, and transcription. Most microvesicles contain the so-called "heat-shock proteins" hsp70 and hsp90, which can facilitate interactions with cells of the immune system. Finally, tetraspanin proteins, including CD9, CD37, CD63 and CD81 are one of the most abundant protein families found in microvesicle membranes. Many of these proteins may be involved in the sorting and selection of specific cargos to be loaded into the lumen of the microvesicle or its membrane.
Other than lipids and proteins, microvesicles are enriched with nucleic acids including messenger RNA and microRNA. The identification of RNA molecules in microvesicles supports the hypothesis that they are a biological vehicle for the transfer of nucleic acids and subsequently modulate the target cell's protein synthesis. Messenger RNA transported from one cell to another through microvesicles can be translated into proteins, conferring new function to the target cell. The discovery that microvesicles may shuttle specific mRNA and miRNA suggests that this may be a new mechanism of genetic exchange between cells. Exosomes produced by cells exposed to oxidative stress can mediate protective signals, reducing oxidative stress in recipient cells, a process which is proposed to depend on exosomal RNA transfer. These RNAs are specifically targeted to microvesicles, in some cases containing detectable levels of RNA that is not found in significant amounts in the donor cell.
Because the specific proteins, mRNAs, and miRNAs in microvesicles are highly variable, it is likely that these molecules are specifically packaged into vesicles using an active sorting mechanism. At this point, it is unclear exactly which mechanisms are involved in packaging soluble proteins and nucleic acids into microvesicles.