Microvesicle
Microvesicles (ectosomes, or microparticles) are a type of extracellular vesicle (EV) that are released from the cell membrane.[1] In multicellular organisms, microvesicles and other EVs are found both in tissues (in the interstitial space between cells) and in many types of body fluids.[2] Delimited by a phospholipid bilayer,[3][4] microvesicles can be as small as the smallest EVs (30 nm in diameter) 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.[5]
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.[6][7][8][9] Microvesicles may also remove misfolded proteins, cytotoxic agents and metabolic waste from the cell. Changes in microvesicle levels may indicate diseases including cancer.[10][11]
Formation and contents
Different cells can release microvesicles from the plasma membrane. Sources of microvesicles include
Platelets play an important role in maintaining hemostasis: they promote
Endothelial microparticles
Endothelial microparticles are small
The microparticle consists of a
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,[14] and pre-eclampsia[15] 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.[16]
Endothelial microparticles have been found to prevent apoptosis in recipient cells by inhibiting the p38 pathway via inactivating mitogen-activated protein kinase (MKP)-1. Uptake of endothelial micoparticles is Annexin I/Phosphatidylserine receptor dependant.[17]
Microparticles are derived from many other cell types.[18]
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,
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,
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
Once formed, both microvesicles and exosomes (collectively called extracellular vesicles) 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.[21]
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
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.[23]
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
Microvesicle membranes consist mainly of
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.[22][24][25][26] 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.[27]
Other than lipids and proteins, microvesicles are enriched with nucleic acids (e.g., messenger RNA (
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.[20][30]
Role on target cells
Once released from their cell of origin, microvesicles interact specifically with cells they recognize by binding to cell-type specific, membrane-bound receptors. Because microvesicles contain a variety of surface molecules, they provide a mechanism for engaging different cell receptors and exchanging material between cells. This interaction ultimately leads to fusion with the target cell and release of the vesicles' components, thereby transferring bioactive molecules, lipids, genetic material, and proteins. The transfer of microvesicle components includes specific mRNAs and proteins, contributing to the proteomic properties of target cells.[26] microvesicles can also transfer miRNAs that are known to regulate gene expression by altering mRNA turnover.[20][21][24][31]
Mechanisms of signaling
Degradation
In some cases, the degradation of microvesicles is necessary for the release of
Fusion
Proteins on the surface of the microvesicle will interact with specific molecules, such as integrin, on the surface of its target cell. Upon binding, the microvesicle can fuse with the plasma membrane. This results in the delivery of nucleotides and soluble proteins into the cytosol of the target cell as well as the integration of lipids and membrane proteins into its plasma membrane.[3]
Internalization
Microvesicles can be endocytosed upon binding to their targets, allowing for additional steps of regulation by the target cell. The microvesicle may fuse, integrating lipids and membrane proteins into the endosome while releasing its contents into the cytoplasm. Alternatively, the endosome may mature into a lysosome causing the degradation of the microvesicle and its contents, in which case the signal is ignored.[3]
Transcytosis
After internalization of microvesicle via endocytosis, the endosome may move across the cell and fuse with the plasma membrane, a process called
Contact dependent signaling
In this form of signaling, the microvesicle does not fuse with the plasma membrane or engulfed by the target cell. Similar to the other mechanisms of signaling, the microvesicle has molecules on its surface that will interact specifically with its target cell. There are additional surface molecules, however, that can interact with receptor molecules which will interact with various signaling pathways.
Relevance in disease
Cancer
Promoting aggressive tumor phenotypes
The oncogenic receptor ECGFvIII, which is located in a specific type of aggressive glioma tumor, can be transferred to a non-aggressive population of tumor cells via microvesicles. After the oncogenic protein is transferred, the recipient cells become transformed and show characteristic changes in the expression levels of target genes. It is possible that transfer of other mutant oncogenes, such as HER2, may be a general mechanism by which malignant cells cause cancer growth at distant sites.[20][31] Microvesicles from non-cancer cells can signal to cancer cells to become more aggressive. Upon exposure to microvesicles from tumor-associated macrophages, breast cancer cells become more invasive in vitro.[33]
Promoting angiogenesis
Angiogenesis, which is essential for tumor survival and growth, occurs when endothelial cells proliferate to create a matrix of blood vessels that infiltrate the tumor, supplying the nutrients and oxygen necessary for tumor growth. A number of reports have demonstrated that tumor-associated microvesicles release proangiogenic factors that promote endothelial cell proliferation, angiogenesis, and tumor growth. Microvesicles shed by tumor cells and taken up by endothelial cells also facilitate angiogenic effects by transferring specific mRNAs and miRNAs.[21]
Involvement in multidrug resistance
When anticancer drugs such as
Interference with antitumor immunity
Microvesicles from various tumor types can express specific cell-surface molecules (e.g. FasL or CD95) that induce
Impact on tumor metastasis
Degradation of the extracellular matrix is a critical step in promoting tumor growth and metastasis. Tumor-derived microvesicles often carry protein-degrading enzymes, including matrix metalloproteinase 2 (
Cellular Origin of Microvesicles
The release of microvesicles has been shown from endothelial cells,
Cardiovascular disease
Microvesicles are involved in cardiovascular disease initiation and progression. Microparticles derived from monocytes aggravate atherosclerosis by modulating inflammatory cells.[38] Additionally, microvesicles can induce clotting by binding to clotting factors or by inducing the expression of clotting factors in other cells.[39] Circulating microvesicles isolated from cardiac surgery patients were found to be thrombogenic in both in vitro assays and in rats. Microvesicles isolated from healthy individuals did not have the same effects and may actually have a role in reducing clotting.[40][39] Tissue factor, an initiator of coagulation, is found in high levels within microvesicles, indicating their role in clotting.[41] Renal mesangial cells exposed to high glucose media release microvesicles containing tissue factor, having an angiogenic effect on endothelial cells.[42]
Inflammation
Microvesicles contain cytokines that can induce
Neurological disorders
Microvesicles seem to be involved in a number of neurological diseases. Since they are involved in numerous vascular diseases and inflammation,
Clinical applications
Detection of cancer
Tumor-associated microvesicles are abundant in the blood, urine, and other body fluids of patients with cancer, and are likely involved in tumor progression. They offer a unique opportunity to noninvasively access the wealth of biological information related to their cells of origin. The quantity and molecular composition of microvesicles released from
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.[51][52]
Conversely, microvesicles processed from a tumor cell are involved in the transport of cancer proteins and in delivering
Tumor microvesicles also carry tumor
Microvesicles and Rheumatoid arthritis
Biological markers for disease
In addition to detecting cancer, it is possible to use microvesicles as biological markers to give prognoses for various diseases. Many types of neurological diseases are associated with increased level of specific types of circulating microvesicles. For example, elevated levels of phosphorylated tau proteins can be used to diagnose patients in early stages of Alzheimer's. Additionally, it is possible to detect increased levels of CD133 in microvesicles of patients with epilepsy.[44]
Mechanism for drug delivery
Circulating microvesicles may be useful for the delivery of drugs to very specific targets. Using electroporation or centrifugation to insert drugs into microvesicles targeting specific cells, it is possible to target the drug very efficiently.[32] This targeting can help by reducing necessary doses as well as prevent off-target side effects. They can target anti-inflammatory drugs to specific tissues.[43] Additionally, circulating microvesicles can bypass the blood–brain barrier and deliver their cargo to neurons while not having an effect on muscle cells. The blood-brain barrier is typically a difficult obstacle to overcome when designing drugs, and microvesicles may be a means of overcoming it.[32] Current research is looking into efficiently creating microvesicles synthetically, or isolating them from patient or engineered cell lines.[53]
See also
- International Society for Extracellular Vesicles
- Journal of Extracellular Vesicles
- Exocytosis
- Membrane vesicle trafficking
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Further reading
- Nilsson, J; Skog, J; Nordstrand, A; Baranov, V; Mincheva-Nilsson, L; Breakefield, X O; Widmark, A (2009). "Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer". British Journal of Cancer. 100 (10): 1–5. PMID 19401683.
- Al-Nedawi, Khalid; Meehan, Brian; Rak, Janusz (2009). "Microvesicles: messengers and mediators of tumor progression". Cell Cycle. 8 (13): 2014–8. PMID 19535896.