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3 EV (Extracellular Vesicle)-associated miRNAs as Biomarkers of Toxicity
Ryuichi Ono1*, Yusuke Yoshioka2, Yusuke Furukawa1, Mie Naruse1,3, Makiko Kuwagata1, Takahiro Ochiya1,2,4, Satoshi Kitajima1, and Yoko Hirabayashi5
1 Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences (NIHS)
2 Division of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University
3 Central Animal Division, National Cancer Center Research Institute
4 Division of Molecular and Cellular Medicine, National Cancer Center Research Institute
5 Center for Biological Safety and Research, National Institute of Health Sciences (NIHS)
Introduction
Exosomes were originally discovered in 1983, as membrane vesicles of approximately 100 nm in diameter with a lipid bilayer structure. These vesicles are secreted by reticulocytes (Harding and Stahl 1983; Pan and Johnstone 1983). They were initially thought to be a “trash bag” in which cells could eliminate excess proteins; however, from 2007 on great advances in exosome research were made, as it was shown that microRNAs (miRNAs) in exosomes could be transferred between cells and played important roles in many physiological and pathological processes (Valadi et al. 2007; Pegtel et al. 2010; Mittelbrunn et al. 2011; Hergenreider et al. 2012; Montecalvo et al. 2012).
Exosomes are secreted into body fluids from various types of cells and organs. Recent studies have demonstrated that exosomes secreted by tumor cells are transported to surrounding cells and participate in metastasis and infiltration. Since these tumor-derived exosomes containing cancer cell-specific miRNAs and mRNAs are secreted into body fluids such as blood, urine, ascites, amniotic fluid, bronchoalveolar lavage, and tears, the miRNAs and mRNAs in cancer cell-derived exosomes have come to be used as diagnostic biomarkers for early stage cancers (Thery et al. 2002; Logozzi et al. 2009; Lu et al. 2009; Rabinowits et al. 2009; Montecalvo et al. 2012; Peinado et al. 2012). In parallel, miRNAs contained in exosomes released into the blood from tissues and organs in response to adverse events, such as exposure to chemical substances and drugs, are expected to be useful as novel biomarkers for toxicity assessment.
In this chapter we will introduce the latest findings on exosomes, including the newly appreciated biological significance of exosomes, and will explain the potential use of exosomes as biomarkers of toxicity.
The Classification of Extracellular Vesicles (EVs)
Various particles are secreted by cells and released into body fluids such as blood, urine, ascites, amniotic fluid, bronchoalveolar lavage, and tears; the International Society for Extracellular Vesicles (ISEV) has named these particles “extracellular vesicles” (EVs) (Thery et al. 2002; Witwer et al. 2017). EVs are divided into three subtypes: exosomes, microvesicles (MVs), and apoptotic bodies. This classification is based on their size and on the biosynthetic pathways by which they are generated (see Figure 3.1 and Table 3.1; also Colombo et al. 2014).
Figure 3.1 Schematic illustration of extracellular vesicles (EVs). EVs include exosomes, microvesicles and apoptotic bodies. MVB: multivesicular body.
Exosomes are thought to derive from intraluminal vesicles through the fusion of an intermediate endocytic compartment, the multivesicular body (MVB), with the plasma membrane (Witwer et al. 2013; Cufaro et al. 2019). The MVB contains vesicles that bind either to lysosomes, to degrade their contents, or to the plasma membrane. The latter produces the release of intraluminal vesicles defined as exosomes into extracellular space (Harding and Stahl 1983; Pan et al. 1985).
As already mentioned, exosomes are approximately 100 nm in diameter; hence they are smaller than MVs (Witwer et al. 2013). Exosome membrane proteins are enriched in heat shock proteins (HSP70, HSP90), integrins (LFA-1), proteins involved in MVB formation (ALIX, TSG101), tetraspanins (CD9, CD63, CD81, CD82, and CD151), immunostimulatory molecules (MHC class I/II proteins), lipid-related proteins, and phospholipases (Conde-vancells et al. 2008; Subra et al. 2010).
Table 3.3 Main characteristics of exosomes, microvesicles (MV), and apoptotic bodies.
| Exosomes | Microvesicles | Apoptotic Bodies | |
|---|---|---|---|
| Origin | Endocytic pathway | Plasma membrane | Plasma membrane |
| Size | 40–120 nm | 50–1000 nm | 500–2000 nm |
| Function | Intercellular communication | Intercellular communication | Facilitate phagocytosis |
| Markers | Alix, Tsg101, tetraspanins | Selectins, integrins, CD proteins, DNA, RNA40 ligand | Histones, annexin V |
| Contents | Protein, DNA, RNA | Protein, DNA, RNA |
Nuclear
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