ReviewExosomes and exosomal miRNAs in cardiovascular protection and repair
Graphical abstract
Introduction
It has been known for some considerable time that when cells undergo apoptosis small vesicles, known as apoptotic bodies, form [1]. It was initially thought that all particles smaller than 4 μm fell into this category and were, essentially, debris that was just a means of packaging the remnants of the dead cells in a way that would not cause any collateral damage to other cells in the vicinity, a form of “rubbish collection” [2]. However, evidence has emerged that the smallest of these extracellular vesicles (EVs), generally those in the size range of 30 nm to 1 μm, are not necessarily released during cell death and have a biological function. Exosomes are some of the smallest of these EVs and are often described as having a size of the order of 30–100 nm, while microparticles (MPs) are generally between 100 and 1 μm. These size ranges, however, are not considered absolute [3]. The mechanism of release of these different particles is also different, in that exosomes are produced through the endosomal pathway, whereas MPs are released through budding from the cell membrane. Exosomes carry on their surface some of the cell surface markers of their cell of origin and evidence is mounting that they are able to interact with the cell surface receptors on neighbouring and possibly also distant cells, in an almost hormonal fashion [4]. In addition, the vesicular nature of exosomes means that they are able to carry a cargo, which includes proteins [5], messenger RNAs (mRNAs) and microRNAs (miRNAs) [6], and to transfer these cargos to recipient cells, thus contributing to cell-to-cell communication. The EV cargo might considerably vary in function of the producing cell type and its “health status”, thus producing very different functional results in the incorporating cells.
This review will focus on exosomes and exosomal miRNAs and discuss their roles in cardiovascular protection and regeneration.
Section snippets
Exosome biogenesis, release and uptake
Exosomes are a subtype of membrane vesicles released from the endocytic compartment of live cells. Exosome biogenesis is exemplified in Fig. 1. The endocytic vesicles originate from highly dynamic membrane compartments involved in the internalization of extracellular ligands following the invagination of plasma membrane. Surface proteins found on the plasma membrane may be transferred to the inner membrane (towards the lumen) of these endocytic vesicles during the process. Inward budding of the
Exosome cargos
As shown in Fig. 1, a wide range of cargo is transported within exosomes including mRNA, miRNA (further described below), cytoskeletal elements (e.g. actins), proteins, enzymes, molecular chaperones and signalling molecules. In fact, Valadi et al. identified 1300 mRNAs and 120 miRNAs in exosomes from mast cells, many of which were not expressed in the donor cell cytoplasm, indicating that the RNA was targeted to exosomes via a selective mechanism [18]. They also found that the RNA from mast
Methods for exosome characterization
Characterizing and observing exosomes is challenging, given their small size. The upper limit of their size range is below the threshold that instruments that would be classically used for their characterization, such as a flow cytometer, can accurately distinguish from noise, or individual particles from each other. This means that the flow cytometer cannot be used to observe individual exosomes. One therefore needs to be more creative in characterizing exosomes and use several different
Exosomes in cardiovascular cell-to-cell communication
Evidence that exosomes are secreted by cardiac and vascular cells and stem cells in culture have emerged [22], [40], [41], [42]. Moreover, exosomes have been shown to mediate communication between endothelial cells (ECs) and smooth muscle cells (SMCs) [43], ECs and pericytes (A Caporali and C Emanueli, unpublished data, 2014), cardiac myocytes and ECs [44] and fibroblasts and cardiac myocytes [20]. Fig. 2 summarized the role of exosomes and exosomal miRNAs in cardiovascular cell-to-cell
Translational perspectives: exosomes as new therapeutics and clinical biomarkers
Exosomes are naturally adapted for the transport and intercellular delivery of proteins and nucleic acids. This makes them particularly attractive as pharmaceutical delivery agents. Moreover, due to their biophysical properties, exosomes are easy to isolate and their RNA and protein contents manipulated [56], [57]. Therefore, in addition to being used as therapeutic entities themselves, both natural exosomes and exosome-mimetic nanovesicles are regarded as possible therapeutic Trojan Horses to
Funding and Acknowledgement
The work was funded by the Leducq Transatlantic Network in Vascular microRNAs (MIRVAD) and the British Heart Foundation (BHF) Regenerative Medicine Centres (both to CE); the National Institute of Health (NIH: R01HL124187) Bristol Cardiovascular Biomedical Research Unit (BRU) to GDA and by the National Institute of Health (NIH) and the American Heart Association (AHA: 12SDG12160052) funded grants to SS. CE is a BHF Senior Research Fellow; GDA in a BHF Chair of Cardiac Surgery and a NIHR Senior
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