Microvesicles (ectosomes, or microparticles) are a type of extracellular vesicle (EV) that are released from the

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

. 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. Delimited by a phospholipid bilayer, 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 In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

miRNA Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcri ...

, 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 In biology, cell signaling (cell signalling in British English) is the Biological process, process by which a Cell (biology), cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all Cell (biol ...

. Like other EVs, they have been implicated in numerous physiologic processes, including anti-tumor effects, tumor immune suppression, metastasis, tumor-stroma interactions,

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

, 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 Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...

, neutrophils, tumor cells and

placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...

. Platelets play an important role in maintaining hemostasis: they promote

thrombus A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...

growth, and thus they prevent loss of blood. Moreover, they enhance immune response, since they express the molecule CD154 (

CD40L CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 (protein), CD40 on antigen-presenting cells (APC), which leads to many e ...

). 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 A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

are incapable of producing IgG, IgE, or IgA as a response to

antigens In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. An ...

. 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 Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood is com ...

. The microparticle consists of a

plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

surrounding a small amount of

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

. The membrane of the endothelial microparticle contains receptors and other cell surface

molecule A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...

s which enable the identification of the endothelial origin of the microparticle, and allow it to be distinguished from microparticles from other cells, such as

platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...

s. 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

disease A disease is a particular abnormal condition that adversely affects the structure or function (biology), function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical condi ...

s, including

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

and cardiovascular disorders, and

pre-eclampsia Pre-eclampsia is a multi-system disorder specific to pregnancy, characterized by the new onset of hypertension, high blood pressure and often a significant amount of proteinuria, protein in the urine or by the new onset of high blood pressure a ...

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 Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

. Endothelial microparticles have been found to prevent

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

in recipient cells by inhibiting the p38 pathway via inactivatin
mitogen-activated protein kinase (MKP)-1
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,

-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 Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, re ...

lipids Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins Vitamin A, A, Vitamin D, D, Vitamin E, E and Vitamin K, K), monoglycerides, diglycerides, phospholipids, and others. The fu ...

, and

nucleic acids Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nucleic a ...

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 Exocytosis is a term for the active transport process that transports large molecules from cell to the extracellular area. Hormones, proteins and neurotransmitters are examples of large molecules that can be transported out of the cell. Exocytosis ...

, exosomes are initially formed by

endocytosis Endocytosis is a cellular process in which Chemical substance, substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a Vesicle (biology and chem ...

. Exosomes are formed by invagination within a cell to create an intracellular vesicle called an

endosome Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of the endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membra ...

, or an endocytic vesicle. In general, exosomes are formed by segregating the cargo (e.g., lipids, proteins, and nucleic acids) within the endosome. Once formed, the endosome combines with a structure known as a multivesicular body (MVB). The MVB containing segregated endosomes ultimately fuses with the plasma membrane, resulting in exocytosis of the exosomes. 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 Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...

, and

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

Mechanism of shedding

There are three mechanisms which lead to release of vesicles into the extracellular space. First of these mechanisms is

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 Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typi ...

. aminophospholipids, phosphatidylserine, and

phosphatidylethanolamine Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. S-Adenosyl methionine, ''S''-Ade ...

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 A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

, Golgi,

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

, or a nucleus with its associated DNA. Microvesicle membranes consist mainly of membrane lipids and

membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...

s. 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 (APCs), such as

B cells B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...

and

dendritic cells A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...

, are enriched in proteins necessary for adaptive immunity, while microvesicles released from tumors contain proapoptotic molecules and oncogenic receptors (e.g. EGFR). 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 Hsp90 (heat shock protein 90) is a chaperone (protein), chaperone protein that assists other proteins to protein folding, fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of ...

, 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 (e.g., 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 Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

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.

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. microvesicles can also transfer miRNAs that are known to regulate gene expression by altering mRNA turnover.

Mechanisms of signaling

Degradation

In some cases, the degradation of microvesicles is necessary for the release of signaling molecules. During microvesicle production, the cell can concentrate and sort the signaling molecules which are released into the extracellular space upon microvesicle degradation. Dendritic cells, macrophage and microglia derived microvesicles contain proinflammatory cytokines and

neurons A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

and

endothelial cells The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...

release

growth factors A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...

using this mechanism of release.

Fusion

Proteins on the surface of the microvesicle will interact with specific molecules, such as

integrin Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, o ...

, 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.

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 A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...

causing the degradation of the microvesicle and its contents, in which case the signal is ignored.

=Transcytosis

= After internalization of microvesicle via endocytosis, the endosome may move across the cell and fuse with the plasma membrane, a process called transcytosis. This results in the ejection of the microvesicle back into the extracellular space or may result in the transportation of the microvesicle into a neighboring cell. This mechanism might explain the ability of microvesicle to cross biological barriers, such as the blood brain barrier, by moving from cell to cell.

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. This mechanism of action can be used in processes such as antigen presentation, where MHC molecules on the surface of microvesicle can stimulate an immune response. Alternatively, there may be molecules on microvesicle surfaces that can recruit other proteins to form extracellular protein complexes that may be involved in signaling to the target cell.

Relevance in disease

Cancer

Promoting aggressive tumor phenotypes

The oncogenic receptor ECGFvIII, which is located in a specific type of aggressive

glioma A glioma is a type of primary tumor that starts in the glial cells of the brain or spinal cord. They are malignant but some are extremely slow to develop. Gliomas comprise about 30% of all brain and central nervous system tumors and 80% of ...

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. 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''.

Promoting angiogenesis

Angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

, 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.

Involvement in multidrug resistance

When anticancer drugs such as doxorubicin accumulate in microvesicles, the drug's cellular levels decrease. This can ultimately contribute to the process of drug resistance. Similar processes have been demonstrated in microvesicles released from

cisplatin Cisplatin is a chemical compound with chemical formula, formula ''cis''-. It is a coordination complex of platinum that is used as a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, c ...

-insensitive cancer cells. Vesicles from these tumors contained nearly three times more cisplatin than those released from cisplatin-sensitive cells. For example, tumor cells can accumulate drugs into microvesicles. Subsequently, the drug-containing microvesicles are released from the cell into the extracellular environment, thereby mediating resistance to chemotherapeutic agents and resulting in significantly increased tumor growth, survival, and

metastasis Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

Interference with antitumor immunity

Microvesicles from various tumor types can express specific cell-surface molecules (e.g. FasL or CD95) that induce T-cell apoptosis and reduce the effectiveness of other immune cells. microvesicles released from lymphoblastoma cells express the immune-suppressing protein latent membrane protein-1 (LMP1), which inhibits T-cell proliferation and prevents the removal of circulating tumor cells (CTCs). As a consequence, tumor cells can turn off T-cell responses or eliminate the antitumor immune cells altogether by releasing microvesicles. the combined use of microvesicles and 5-FU resulted in enhanced chemosensitivity of squamous cell carcinoma cells more than the use of either 5-FU or microvesicle alone

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 ( MMP-2), MMP-9, and urokinase-type plasminogen activator ( uPA). By releasing these proteases, tumor cells can degrade the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...

and invade surrounding tissues. Likewise, inhibiting MMP-2, MMP-9, and uPA prevents microvesicles from facilitating tumor metastasis. Matrix digestion can also facilitate angiogenesis, which is important for tumor growth and is induced by the horizontal transfer of RNAs from microvesicles.

Cellular Origin of Microvesicles

The release of microvesicles has been shown from endothelial cells, vascular smooth muscle cells,

platelets Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cyto ...

, white blood cells (e.g.

leukocytes White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

and

lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), and ...

), and

red blood cells Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...

. Although some of these microvesicle populations occur in the blood of healthy individuals and patients, there are obvious changes in number, cellular origin, and composition in various disease states. It has become clear that microvesicles play important roles in regulating the cellular processes that lead to disease pathogenesis. Moreover, because microvesicles are released following apoptosis or cell activation, they have the potential to induce or amplify disease processes. Some of the inflammatory and pathological conditions that microvesicles are involved in include

cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...

, neurodegenerative disorders,

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

, and rheumatic diseases.

Cardiovascular disease

Microvesicles are involved in cardiovascular disease initiation and progression. Microparticles derived from monocytes aggravate

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...

by modulating inflammatory cells. Additionally, microvesicles can induce clotting by binding to clotting factors or by inducing the expression of clotting factors in other cells. 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. Tissue factor, an initiator of coagulation, is found in high levels within microvesicles, indicating their role in clotting. Renal mesangial cells exposed to high glucose media release microvesicles containing tissue factor, having an angiogenic effect on endothelial cells.

Inflammation

Microvesicles contain cytokines that can induce

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

via numerous different pathways. These cells will then release more microvesicles, which have an additive effect. This can call neutrophils and

to the area, resulting in the aggregation of cells. However, microvesicles also seem to be involved in a normal physiological response to disease, as there are increased levels of microvesicles that result from pathology.

Neurological disorders

Microvesicles seem to be involved in a number of neurological diseases. Since they are involved in numerous vascular diseases and inflammation, strokes and

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

seem to be other diseases for which microvesicles are involved. Circulating microvesicles seem to have an increased level of phosphorylated tau proteins during early stage

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. Similarly, increased levels of CD133 are an indicator of

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

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

malignant Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...

cells varies considerably compared with those released from normal cells. Thus, the concentration of plasma microvesicles with molecular markers indicative of the disease state may be used as an informative blood-based biosignature for cancer. Microvesicles express many membrane-bound proteins, some of which can be used as tumor biomarkers. Several tumor markers accessible as proteins in blood or urine have been used to screen and diagnose various types of cancer. In general, tumor markers are produced either by the tumor itself or by the body in response to the presence of cancer or some inflammatory conditions. If a tumor marker level is higher than normal, the patient is examined more closely to look for cancer or other conditions. For example, CA19-9, CA-125, and CEA have been used to help diagnose pancreatic, ovarian, and

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. ...

malignancies, respectively. However, although they have proven clinical utility, none of these tumor markers are highly sensitive or specific. Clinical research data suggest that tumor-specific markers exposed on microvesicles are useful as a clinical tool to diagnose and monitor disease. Research is also ongoing to determine if tumor-specific markers exposed on microvesicles are predictive for therapeutic response. Also published as Also published as 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 Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcr ...

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

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 Fas ligand (FasL, also known as CD95L or Apo-1L) is a type-II transmembrane protein in the tumor necrosis factor (TNF) superfamily. It binds to the Fas receptor (CD95) to induce apoptosis, and also activates non-apoptotic pathways such as NF-κB ...

and

TRAIL A trail, also known as a path or track, is an unpaved lane or a small paved road (though it can also be a route along a navigable waterways) generally not intended for usage by motorized vehicles, usually passing through a natural area. Ho ...

. They prevent differentiation of

. Tumor microvesicles also carry tumor

antigen In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

, so they can be an instrument for developing tumor vaccines. Circulating

and segments of

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

in all

body fluids Body fluids, bodily fluids, or biofluids, sometimes body liquids, are liquids within the Body (biology), body of an organism. In lean healthy adult men, the total body water is about 60% (60–67%) of the total Human body weight, body weight; it ...

can be potential markers for tumor diagnostics.

Microvesicles and Rheumatoid arthritis

Rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

is a chronic systemic

autoimmune disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...

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 Synovial fluid, also called synovia, elp 1/sup> is a viscous, non-Newtonian fluid found in the cavities of synovial joints. With its egg white–like consistency, the principal role of synovial fluid is to reduce friction between the articul ...

. 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 Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

that contribute to joint inflammation and bone and

cartilage Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...

destruction, because they have the ability to transform themselves into

osteoclasts An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated ...

that destroy bone tissue. Synthesis of

reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...

, 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.

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.

Mechanism for drug delivery

Circulating microvesicles may be useful for the delivery of drugs to very specific targets. Using electroporation or

centrifugation Centrifugation is a mechanical process which involves the use of the centrifugal force to separate particles from a solution according to their size, shape, density, medium viscosity and rotor speed. The denser components of the mixture migrate ...

to insert drugs into microvesicles targeting specific cells, it is possible to target the drug very efficiently. 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. Additionally, circulating microvesicles can bypass the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

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. Current research is looking into efficiently creating microvesicles synthetically, or isolating them from patient or engineered cell lines. Microvesicles used in therapeutic genome editing appoaches are sometimes called a “gesicle”, especially if used to package/deliver the

Cas9 Cas9 (CRISPR associated protein 9, formerly called Cas5, Csn1, or Csx12) is a 160 dalton (unit), kilodalton protein which plays a vital role in the immunological defense of certain bacteria against DNA viruses and plasmids, and is heavily utili ...

RNP complex."gesicle" on wiktionary.org
/ref>

References

External links

Vesiclepedia—A database of molecules identified in extracellular vesicles

ExoCarta—A database of molecules identified in exosomes

International Society for Extracellular Vesicles

Resource on the detection of circulating microvesicles
Cell biology Vesicles Medical diagnosis Nanotechnology