Research on extracellular vesicles (EVs) has been advancing rapidly. The number of scientific papers on EVs published in 2011 was approximately 200, which increased to more than 1,000 in 2016. During this time, several researchers have suggested the involvement of EVs in the cell’s physiology and pathogenic mechanisms.
EVs are classified into at least two general categories: exosomes derived from endosomes, and microvesicles derived from plasma membrane. Separating these two classes of EV through standard differential centrifugation is difficult. In practice, EVs not settling at 10,000×g are called “small EVs,” which are mainly composed of exosomes.1
Exosomes are small-membrane vesicles, approximately 30–100 nm in diameter, which are secreted by various cells and present in most body fluids and in many cell culture supernatants. Exosomes arise within intracellular vesicles, called "multi-vesicular endosomes," and are released into the extracellular space through the fusion of multi-vesicular endosomes with the cell membrane.
Exosomes contain proteins from secretory cells, including those involved in intracellular transport, proteins originating from cell membranes, and RNAs. Exosomes also contain the cell membrane of secretory cells and lipids from the endosome membrane, for example, cholesterol and sphingomyelin.2
For years, scientists believed that exosomes were involved in the release of unimportant cell contents. However, exosomes are lately believed to mediate cell-cell communication through the transportation of lipids, proteins, and RNAs. Exosomes have also attracted attention for possible clinical applications, including diagnostic biomarkers and possibly therapeutics.
Given these potentially high-value applications, exosome research now encompasses most biomedical research, including immunology, neuroscience, oncology, endocrinology, and cardiovascular research.
Exosome activity
For example, immune cell–derived exosomes contain antigen peptide/MHC complexes and various antigens, which suggests that exosomes might regulate activation or inactivation of immune cells and the exchange of antigenic information between such cells.3 In the nervous system, exosomes are involved in regulating neural circuits4 and in the extracellular release of proteins implicated in neurodegenerative diseases.5
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A better understanding of the unique role of exosomes is driving widespread interest in the extracellular vesicles. Exosomes released by cancer cells contain biomolecules related to angiogenesis and immune evasion, suggesting that they might promote microenvironments optimal for cancer cell growth and progression.6 Additionally, adhesion molecules on the surface of cancer cell exosomes may determine the destination of cancer metastasis.7
Recently, researchers found that exosomes released from adipocytes regulate hepatic gene expression.8 Furthermore, since viruses leave cells through the same pathway as exosome production, bacteria and parasites infecting cells may regulate activities of pathogens infecting other cells via exosomes.9,10
Most exosome activity described herein is mediated by secretory cell-derived biomolecules contained in exosomes. Since secretory cell mRNAs and miRNAs have been identified in exosomes, the potential involvement of exosomes in horizontal transmission of gene expression between cells has attracted interest.11 Since these RNAs are encapsulated within the lipid bilayer membrane, they are immune to RNase degradation and remain intact in blood or other body fluids long enough to be studied. When exosomes in target cells fuse with the endosome membrane, they release encapsulated RNAs into the cytosol of target cells, where they are translated into proteins while miRNAs suppress translation of target genes. Thus, exosomes regulate gene expression within target cells.
The fact that individual exosomes may carry several thousand mRNAs and miRNAs, tens of thousands of proteins, and a wide variety of lipids would alone justify the current interest in these vesicles. What makes exosomes relevant to modern biology is that the contents of exosomes reflects the biomolecular composition of the cells from which they originate. Most interestingly, exosome biomolecule composition reflects faithfully that which is found within the originator cell, suggesting a critical mechanism for loading exosome-specific biomolecules into exosomes from these parent entities.
These qualities make exosomes attractive as biomarkers and therapeutic targets. Furthermore, while exosome mRNAs incorporated into target cells induce expression of functional proteins, most exosomal miRNAs serve as precursors of functional miRNA through mechanisms that remain unclear but are the subject of intense investigation.
Hence the construction of ExoCarta, a curated database of exosome proteins, RNAs, and lipids. ExoCarta, which is currently undergoing classification by originating cell type, enables the current state of the art in exosome-based proteomics, transcriptomics, and systems biology. Research groups worldwide employ FunRich, a non-commercial software tool, to identify biomolecules that are over-represented in exosomes compared with their levels within originating cells.
As with many nascent, developing areas in the life sciences, the information yet to be discovered far outweighs our knowledge. As more research groups undertake exosome investigations, and with further elucidation of ExoCarta and related data-mining tools, we expect exosomes to become a rich source of information on how cells and larger systems operate. With that understanding, one can expect practical platforms to emerge for diagnosing and treating human disease.
If you want to discover more about exosomes, download our free eBook The Emerging Field of Exosome Research to learn methods and enabling tools for studying and characterizing exosomes, how exosomes are being used as biomarkers and therapeutic targets, and more.
References
1. Kowal J, et al. (2016) Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci USA, 113(8): E968-977.
2. Colombo M, Raposo G, & Thery C (2014). Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol, 30: 255–289.
3. Bobrie A, Colombo M, Raposo G, & Thery C (2011). Exosome secretion: molecular mechanisms and roles in immune responses. Traffic, 12(12): 1659–1668.
4. Bahrini I, Song JH, Diez D, & Hanayama R (2015). Neuronal exosomes facilitate synaptic pruning by upregulating complement factors in microglia. Sci Rep, 5: 7989.
5. Kramer-Albers EM & Hill AF (2016). Extracellular vesicles: interneural shuttles of complex messages. Curr Opin Neurobiol, 39: 101-107. https://www.ncbi.nlm.nih.gov/pubmed/27183381
6. Tkach M & Thery C (2016). Communication by Extracellular Vesicles: Where We Are and Where We Need to Go. Cell, 164(6): 1226–1232.
7. Hoshino A, et al. (2015). Tumour exosome integrins determine organotropic metastasis. Nature, 527(7578): 329-335.
8. Thomou T, et al. (2017). Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature, 542(7642): 450-455.
9. Izquierdo-Useros N, Puertas MC, Borras FE, Blanco J, & Martinez-Picado J (2011). Exosomes and retroviruses: the chicken or the egg? Cell Microbiol, 13(1): 10–17.
10. Regev-Rudzki N, et al. (2013). Cell-cell communication between malaria-infected red blood cells via exosome-like vesicles. Cell, 153(5):1120–1133. 7
11. Valadi H, et al. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol, 9(6): 654–659.