Elsevier

Vascular Pharmacology

Volume 71, August 2015, Pages 24-30
Vascular Pharmacology

Review
Exosomes and exosomal miRNAs in cardiovascular protection and repair

https://doi.org/10.1016/j.vph.2015.02.008Get rights and content

Abstract

Cell–cell communication between cardiac and vascular cells and from stem and progenitor cells to differentiated cardiovascular cells is both an important and complex process, achieved through a diversity of mechanisms that have an impact on cardiovascular biology, disease and therapeutics. In recent years, evidence has accumulated suggesting that extracellular vesicles (EVs) are a new system of intercellular communication. EVs of different sizes are produced via different biogenesis pathways and have been shown to be released and taken up by most of known cell types, including heart and vascular cells, and stem and progenitor cells. This review will focus on exosomes, the smallest EVs (up to 100 nm in diameter) identified so far. Cells can package cargoes consisting of selective lipids, proteins and RNA in exosomes and such cargoes can be shipped to recipient cells, inducing expressional and functional changes. This review focuses on exosomes and microRNAs in the context of cardiovascular disease and repair. We will describe exosome biogenesis and cargo formation and discuss the available information on in vitro and in vivo exosomes-based cell-to-cell communication relevant to cardiovascular science. The methods used in exosome research will be also described. Finally, we will address the promise of exosomes as clinical biomarkers and their impact as a biomedical tool in stem cell-based cardiovascular therapeutics.

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

References (60)

  • E. van der Pol

    Innovation in detection of microparticles and exosomes

    J Thromb Haemost

    (2013)
  • E. van der Pol

    Particle size distribution of exosomes and microvesicles determined by transmission electron microscopy, flow cytometry, nanoparticle tracking analysis, and resistive pulse sensing

    J Thromb Haemost

    (2014)
  • X. Wang

    Cardiomyocytes mediate anti-angiogenesis in type 2 diabetic rats through the exosomal transfer of miR-320 into endothelial cells

    J Mol Cell Cardiol

    (2014)
  • A.S. Leroyer

    Cellular origins and thrombogenic activity of microparticles isolated from human atherosclerotic plaques

    J Am Coll Cardiol

    (2007)
  • Z. Giricz

    Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by extracellular vesicles

    J Mol Cell Cardiol

    (2014)
  • P. Mocharla

    AngiomiR-126 expression and secretion from circulating CD34(+) and CD14(+) PBMCs: role for proangiogenic effects and alterations in type 2 diabetics

    Blood

    (2013)
  • R.C. Lai

    Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury

    Stem Cell Res

    (2010)
  • A.G. Ibrahim et al.

    Exosomes as critical agents of cardiac regeneration triggered by cell therapy

    Stem Cell Rep

    (2014)
  • L. Chen

    Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury

    Biochem Biophys Res Commun

    (2013)
  • J.F. Kerr et al.

    Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics

    Br J Cancer

    (1972)
  • S. Elmore

    Apoptosis: a review of programmed cell death

    Toxicol Pathol

    (2007)
  • K.W. Witwer

    Standardization of sample collection, isolation and analysis methods in extracellular vesicle research

    J extracellular vesicles

    (2013)
  • D. Skokos

    Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo

    J Immunol

    (2003)
  • Z.A. Malik

    Cardiac myocyte exosomes: stability, HSP60, and proteomics

    Am J Physiol Heart Circ Physiol

    (2013)
  • H. Valadi

    Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells

    Nat Cell Biol

    (2007)
  • S. Sahoo

    Exosomes from human CD34(+) stem cells mediate their proangiogenic paracrine activity

    Circ Res

    (2011)
  • M.P. Oksvold

    Expression of B-cell surface antigens in subpopulations of exosomes released from B-cell lymphoma cells

    Clin Ther

    (2014)
  • L. Zakharova et al.

    T cell exosomes induce cholesterol accumulation in human monocytes via phosphatidylserine receptor

    J Cell Physiol

    (2007)
  • J. Palma

    MicroRNAs are exported from malignant cells in customized particles

    Nucleic Acids Res

    (2012)
  • A.J. O'Loughlin et al.

    Exosomes and the emerging field of exosome-based gene therapy

    Curr Gene Ther

    (2012)
  • Cited by (0)

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