Exosomes are cell-derived vesicles that are present in many and perhaps all biological fluids, including blood, urine, and cultured medium of cell cultures. The reported diameter of exosomes is between 30 and 100 nm, which is larger than LDL, but much smaller than for example red blood cells. Exosomes are either released from the cell when multivesicular bodies fuse with the plasma membrane or they are released directly from the plasma membrane. It is becoming increasingly clear that exosomes have specialized functions and play a key role in, for example, coagulation, intercellular signaling, and waste management. Consequently, there is a growing interest in the clinical applications of exosomes. Exosomes can potentially be used for prognosis, therapy, and biomarkers for health and disease.
First discovered in the maturing mammalian reticulocyte (immature red blood cell) , exosomes were shown to participate in selective removal of many plasma membrane proteins as the reticulocyte becomes a mature red blood cell (erythrocyte). In the reticulocyte, as in most mammalian cells, portions of the plasma membrane are regularly internalized as endosomes, with 50 to 180% of the plasma membrane being recycled every hour. In turn, parts of the membranes of some endosomes are subsequently internalized as smaller vesicles. Such endosomes are called multivesicular bodies because of their appearance, with many small vesicles, or "intralumenal endosomal vesicles," inside the larger body. The intralumenal endosomal vesicles become exosomes if the multivesicular body merges with the cell membrane, releasing the internal vesicles into the extracellular space.
Exosomes contain various molecular constituents of their cell of origin, including proteins and RNA. Although the exosomal protein composition varies with the cell and tissue of origin, most exosomes contain an evolutionary-conserved common set of protein molecules. The RNA molecules in exosomes include mRNA and miRNA. One study suggested that miRNAs in exosomes secreted by mesenchymal stem cells (MSC) are predominantly pre- and not mature miRNAs. Because the authors of this study did not find RNA-induced silencing complex-associated proteins in these exosomes, they suggested that only the pre-miRNAs but not the mature miRNAs in MSC exosomes have the potential to be biologically active in the recipient cells.
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. 
Because of the multidisciplinary research field, detection and isolation difficulties, and different ways of classification, there is currently no consensus about the nomenclature of cell-derived vesicles including exosomes. Consequently, exosomes are also referred to as microvesicles, 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.
Exosomes from red blood cells contain the transferrin receptor which is absent in mature erythrocytes. Dendritic cell-derived exosomes express MHC I, MHC II, and costimulatory molecules and have been proven to be able to induce and enhance antigen-specific T cell responses in vivo. In addition, the first exosome-based cancer vaccination platforms are being explored in early clinical trials. Exosomes can also be released into urine by the kidneys, and their detection might serve as a diagnostic tool. Urinary exosomes may be useful as treatment response markers in prostate cancer. Exosomes secreted from tumour cells can deliver signals to surrounding cells and have been shown to regulate myofibroblast differentiation. Exosomes released from tumors into the blood may also have diagnostic potential. Exosomes are remarkably stable in bodily fluids strengthening their case as reservoirs for disease biomarkers. Patient blood samples stored in biorepositories can be used for biomarker analysis as colorectal cancer cell-derived exosomes spiked into blood plasma could be recovered after 90 days of storage at various temperature.
The isolation and detection of exosomes has proven to be extremely difficult. On the one hand, due to the complexity of body fluids, physical separation of exosomes from cells and similar sized particles is challenging. On the other hand, since the diameter of exosomes is typically below 100 nm and because they have a low refractive index, exosomes are below the detection range of many currently used techniques. Often, functional as well as antigenic assays are applied to derive useful information from multiple exosomes. Well known examples of assays to detect proteins in total populations of exosomes are mass spectrometry and Western blot. However, a limitation of these methods is that contaminants may be present that affect the information obtained from such assays. Preferably, information is derived from single exosomes. Relevant properties of exosomes to detect include size, density, morphology, composition, and zeta potential.
Flow cytometry is probably the most commonly applied optical method to detect exosomes in suspension. Nevertheless, the applicability of flow cytometry to detect single exosomes is still inadequate due to limited sensitivity and potential measurement artifacts such as swarm detection. Other methods to detect single exosomes are atomic force microscopy, nanoparticle tracking analysis, Raman microspectroscopy, resistive pulse sensing, and transmission electron microscopy.
Microarrays are now being used to detect exosomes.
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- http://www.exocarta.org ExoCarta - Database of molecules identified in exosomes
- http://www.microvesicles.org Vesiclepedia - Database of molecules identified in extracellular vesicles
- http://www.exosome.com Exosome.com - Resource on the advances in exosome technology
- http://www.isevmeeting.org - International Society for Extracellular Vesicles (ESEV)
- http://www.asemv.org - American Society for Exosomes and Microvesicles
- http://www.edwinvanderpol.com/research - Resource on the detection of exosomes
- http://www.metves.eu - Research project on the metrological characterisation of micro-vesicles from body fluids
- http://atlas.dmi.unict.it/mirandola - miRandola: Extracellular Circulating microRNAs Database
- http://www.exosomedx.com - Exosome Diagnostics, Inc.
- http://www.exosome-rna.com Exosome RNA