Review articleMicrovesicles in the brain: Biomarker, messenger or mediator?
Introduction
Extracellular vesicles (EVs), firstly described as “platelet dust” by Wolf (Wolf, 1967), have received a great deal of attention during the last decade as a novel approach to detecting diseases and messengers or mediators of disease pathophysiology.
The relatively new term “EVs” includes exosomes and activation- or apoptosis-induced microparticles/microvesicles (MPs/MVs). MPs/MVs measure 100–1000 nm in diameter, apoptotic vesicles are relatively large (up to 4000 nm in diameter) (Lee et al., 2011), whereas exosomes are smaller in size, < 100 nm and are formed and stored within the cell before their release (Théry et al., 2002, Thery et al., 2009, Beyer and Pisetsky, 2010).
Mainly composed of lipids, proteins and nucleic acids, MVs are heterogeneous, differing in size, as well as in phospholipid and protein composition according to the cell origin. MVs are more than just a miniature version of the origin of specific cells. In this regard, certain MV components are selectively enriched compared to their parental cell, and the MV composition and function depend not only on the cellular origin but also on the agonist responsible for MV formation other than the microenvironment of the parental cell (Mause and Weber, 2010).
Some of the triggers responsible for MV release include pro-inflammatory mediators, such as cytokines, thrombin, endotoxins, hypoxia, oxidative injury and shear stress (VanWijk et al., 2003).
MVs have been isolated from biofluids, including pleural effusions (Bard et al., 2004), plasma (Caby et al., 2005, Lässer et al., 2011a), ocular effluent and aqueous humor (Perkumas et al., 2007), breast milk (Lässer et al., 2011a, Admyre et al., 2007), ascites (Dai et al., 2008, Dvorak et al., 1981), amniotic fluid (Asea et al., 2008, Keller et al., 2011), semen (“prostasomes” and “epididymosomes”) (Poliakov et al., 2009, Ronquist and Brody, 1985, Aalberts et al., 2012), saliva (Lässer et al., 2011a, Keller et al., 2011), nasal secretions (Lasser et al., 2011b), cerebrospinal fluid (CSF) (Street et al., 2012), bronchoalveolar lavage (Admyre et al., 2003, Qazi et al., 2010), synovial fluid (Fourcade et al., 1995, Boilard et al., 2010), bile (Masyuk et al., 2010), urine (Raj et al., 2012, Wiggins et al., 1986) and sputum (Porro et al., 2010).
The different biological circumstances under which the formation of MVs has been observed reflect their diverse biogenesis, structure and function. Thus, cellular activation, transformation, stress, or programmed cell death are associated with a different output and nature of vesicular structures (Kulessa et al., 1995). Indeed, it is clear that MVs are heterogeneous, and this has led to the adoption of multiple names for their designation under different experimental settings (Kulessa et al., 1995). In the literature, generic terms have often been used to describe cell-derived vesicles, including “microparticles”. However, it is now clear that they represent a heterogeneous population of discrete entities which include exosomes (Keller et al., 2006), microvesicles (Fader and Colombo, 2009), ectosomes (Morel et al., 2004), membrane particles (Heijnen et al., 1999), exosome-like vesicles (Nomura et al., 2000) and apoptotic vesicles (Janowska-Wieczorek et al., 2001), microparticles (George et al., 1982).
Each population has its own panel of phenotypic and functional characteristics and is generated by different mechanisms (Quesenberry and Aliotta, 2010). For example, “exosomes” have classically been defined as originating from the endosomal compartment by fusion of multivesicular bodies with the plasma membrane, “microvesicles”, “ectosomes” or “shed vesicles/particles” have been thought to originate by direct budding from the plasma membrane (Vickers and Remaley, 2012, Mathivanan et al., 2010), whereas apoptotic vesicles are the result of cell fragmentation during apoptotic cell death (Beyer and Pisetsky, 2010).
Different classes of proteins can be found in different populations of vesicles, including histones in apoptotic vesicles (Thery et al., 2009) and tetraspanins, which show CD9, CD63 and CD81 in exosomes (Morelli et al., 2004). The main protein markers of MVs are surface receptors, integral membrane proteins, as well as cytosolic proteins, some mRNAs, and even miRNAs (Raposo and Stoorvogel, 2013, Piccin et al., 2007, Timár et al., 2013, Colombo et al., 2012). Although several studies have suggested that histones are reliable protein markers of apoptotic bodies (Thery et al., 2009, Thery et al., 2001, Kerr et al., 1972), they could also be present, along with DNA, in MVs (Barteneva et al., 2013, Souza-Schorey and Clancy, 2012) (See Fig. 1).
Section snippets
How to study MVs
Because of the increasing importance of MVs as potential biomarkers, messengers or mediators of disease pathophysiology, several techniques have been developed with the aim of detecting and quantifying MV levels in biological fluids shown to contain MVs.
These include flow cytometry, procoagulant assays, and ELISA-based solid phase capture assays (Lacroix et al., 2012). Among the currently available detection methods, the one most commonly used for counting and characterizing MVs is flow
MVs in the central nervous system (CNS)
Several reports exploiting the biological role of MVs in CNS diseases have so far been focused on MVs derived from platelets, endothelial cells, neurons or glial cells. Cells in the neurovascular unit or its vicinity, including the endothelial lining and neural cells (neurons, astrocytes, oligodendrocytes, and microglia), are also subject to stress by a variety of stimuli (e.g., oxygen radicals, inflammation, ischemia, etc.) known to induce membrane shedding in vascular cells. It is therefore
Modulation of MV production
Once described as inert biological bystanders, it has now been established that MVs actively contribute to the development and progression of numerous pathologies (Roseblade et al., 2013). MVs have thus emerged as novel therapeutic targets in the treatment of diseases, through the modulation of their release (El-Assaad et al., 2014).
In patients with CM, high plasma levels of circulating platelet, erythrocytic, leucocytic and in particular endothelial cell-derived MPs have been detected (Combes
Conclusion
MVs, once regarded merely as cell debris, now seem to be shown to influence a series of physiological and pathological processes. MVs are now emerging as new messengers/biomarkers from a specific tissue undergoing activation or damage.
Because the plasma membrane is the primary sensor of cell interactions with the microenvironment, the identity of circulating MVs of endothelial, platelet and CNS cells origin is a reliable indicator of their activation in CNS diseases such as stroke, TIA, CM and
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
We gratefully thank Mary Victoria Pragnell, B.A., for English language assistance.
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These authors equally contributed to this work.