Exosome (vesicle)

Exosomes are cell-derived vesicles that are present in many and perhaps all eukaryotic fluids, including blood, urine, and cultured medium of cell cultures.[1][2] A sub-type of exosomes, defined as matrix-bound nanovesicles (MBVs), was reported to be present in extracellular matrix (ECM) bioscaffolds (non-fluid).[3] The reported diameter of exosomes is between 30 and 100 nm, which is larger than low-density lipoproteins (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 released directly from the plasma membrane.[4] Evidence is accumulating that exosomes have specialized functions and play a key role in processes such as coagulation, intercellular signaling, and waste management.[1] Consequently, there is a growing interest in the clinical applications of exosomes. Exosomes can potentially be used for prognosis, for therapy, and as biomarkers for health and disease [5].

Background

First discovered in the maturing mammalian reticulocyte (immature red blood cell) ,[6] exosomes were shown to participate in selective removal of many plasma membrane proteins[7] 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.[8] 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.[9]

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 evolutionarily-conserved common set of protein molecules. The protein content of a single exosome, given certain assumptions of protein size and configuration, and packing parameters, can be about 20,000 molecules.[10] The cargo of mRNA and miRNA in exosomes was first discovered at the University of Gothenburg in Sweden.[11] In that study, the differences in cellular and exosomal mRNA and miRNA content was described, as well as the functionality of the exosomal mRNA cargo. Exosomes have also been shown to carry double-stranded DNA.[12]

Exosomes can transfer molecules from one cell to another via membrane vesicle trafficking, thereby influencing the immune system, such as dendritic cells and B cells, and may play a functional role in mediating adaptive immune responses to pathogens and tumors.[13][14] Therefore, scientists that are actively researching the role that exosomes may play in cell-to-cell signaling, often hypothesize that delivery of their cargo RNA molecules can explain biological effects. For example, mRNA in exosomes has been suggested to affect protein production in the recipient cell.[11][15][16] However, another study has suggested that miRNAs in exosomes secreted by mesenchymal stem cells (MSC) are predominantly pre- and not mature miRNAs.[17] 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.

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.[18]

Terminology

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.[1]

Research

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.[19] Exosomes can also be released into urine by the kidneys, and their detection might serve as a diagnostic tool.[20][21][22] Urinary exosomes may be useful as treatment response markers in prostate cancer.[23][24] Exosomes secreted from tumour cells can deliver signals to surrounding cells and have been shown to regulate myofibroblast differentiation.[25] In melanoma, tumor-derived vesicles can enter lymphatics and interact with subcapsular sinus macrophages and B cells in lymph nodes.[26] A recent investigation showed that exosome release positively correlates with the invasiveness of ovarian cancer.[27] Exosomes released from tumors into the blood may also have diagnostic potential. Exosomes are remarkably stable in bodily fluids strengthening their utility as reservoirs for disease biomarkers.[28][29] 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 temperatures.[30]

In malignancies such as cancer, the regulatory circuit which guards exosome homeostasis is co-opted to promote cancer cell survival and metastasis.[31][16]

Urinary exosomes have also proven to be useful in the detection of many pathologies, such as genitourinary cancers and mineralocorticoid hypertension, through their protein and miRNA cargo."[32] [33]

Exosomes and intercellular communication

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 [34]. 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.[15][35] 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.[13][26]

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.[18] It has recently been shown that exosomal protein content may change during the progression of chronic lymphocytic leukemia.[36]

A study hypothesized that intercellular communication of tumor exosomes could mediate further regions of metastasis for cancer. Hypothetically, exosomes can plant tumor information, such as tainted RNA, into new cells to prepare for cancer to travel to that organ for metastasis. The study found that tumor exosomal communication has the ability to mediate metastasis to different organs. Furthermore, even when tumor cells have a disadvantage for replicating, the information planted at these new regions, organs, can aid in the expansion of organ specific metastasis.[37]

Isolation and detection

The isolation and detection of exosomes has proven to be complicated.[1][38] Due to the complexity of body fluids, physical separation of exosomes from cells and similar-sized particles is challenging. Isolation of exosomes using differential ultracentrifugation results in co-isolation of protein and other contaminants and incomplete separation of vesicles from lipoproteins. Combining ultracentrifugation with micro-filtration or a gradient can improve purity.[39][40] Single step isolation of extracellular vesicles by size-exclusion chromatography has been demonstrated to provide greater efficiency for recovering intact vesicles over centrifugation,[41] although a size-based technique alone will not be able to distinguish exosomes from other vesicle types. To isolate a pure population of exosomes a combination of techniques is necessary, based on both physical (e.g. size, density) and biochemical parameters (e.g. presence/absence of certain proteins involved in their biogenesis).

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.[42]

Detection techniques

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. A number of miniaturized systems, exploiting nanotechnology and microfluidics, have been developed to expedite exosome analyses. These new systems include a microNMR device,[43] a nanoplasmonic chip,[44] and an magneto-electrochemical sensor[45] for protein profiling; and an integrated fluidic cartridge for RNA detection.[46] Flow cytometry is an 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.[47] Other methods to detect single exosomes are atomic force microscopy,[48] nanoparticle tracking analysis,[49] Raman microspectroscopy,[50] tunable resistive pulse sensing, and transmission electron microscopy.[47]

Databases

An overview of molecules known to be present in exosomes is provided by the ExoCarta database.[51]

Bioinformatics analysis

Exosomes contain RNA, proteins, lipids and metabolites that is reflective of the cell type of origin. As exosomes contain numerous proteins, RNA and lipids, large scale analysis including proteomics and transcriptomics is often performed. Currently, to analyse these data, non-commercial tools such as FunRich[52] can be used to identify over-represented groups of molecules. With the advent of Next generation sequencing technologies, the research on exosomes have been accelerated in not only cancer but various diseases. Recently, bioinformatics based analysis of RNA-Seq data of exosomes extracted from Trypanosoma cruzi has showed the association of these extracellular vesicles with various important gene products that strengthens the probability of finding biomarkers for Chagas disease.[53][54]

Therapeutics and carriers of drugs

Increasingly, exosomes are being recognized as potential therapeutics as they have the ability to elicit potent cellular responses in vitro and in vivo.[55][56][57] Exosomes mediate regenerative outcomes in injury and disease that recapitulate observed bioactivity of stem cell populations.[58] Mesenchymal stem cell exosomes were found to activate several signaling pathways important in wound healing (Akt, ERK, and STAT3) and bone fracture repair.[59][60] They induce the expression of a number of growth factors (hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF1), nerve growth factor (NGF), and stromal-derived growth factor-1 (SDF1)).[61] Exosomes secreted by human circulating fibrocytes, a population of mesenchymal progenitors involved in normal wound healing via paracrine signaling, exhibited in-vitro proangiogenic properties, activated diabetic dermal fibroblasts, induced the migration and proliferation of diabetic keratinocytes, and accelerated wound closure in diabetic mice in vivo. Important components of the exosomal cargo were heat shock protein-90α, total and activated signal transducer and activator of transcription 3, proangiogenic (miR-126, miR-130a, miR-132) and anti-inflammatory (miR124a, miR-125b) microRNAs, and a microRNA regulating collagen deposition (miR-21).[62] Exosomes can be considered a promising carrier for effective delivery of small interfering RNA due to their existence in body’s endogenous system and high tolerance.[63][64] Patient-derived exosomes have been employed as a novel cancer immunotherapy in several clinical trials.[65]

Exosomes offer distinct advantages that uniquely position them as highly effective drug carriers. Composed of cellular membranes with multiple adhesive proteins on their surface, exosomes are known to specialize in cell–cell communications and provide an exclusive approach for the delivery of various therapeutic agents to target cells.[66] For example, researchers used exosomes as a vehicle for the delivery of cancer drug paclitaxel. They placed the drug inside exosomes derived from white blood cells, which were then injected into mice with drug-resistant lung cancer. Importantly, incorporation of paclitaxel into exosomes increased cytotoxicity more than 50 times as a result of nearly complete co-localization of airway-delivered exosomes with lung cancer cells.[67]

See also

References

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