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Emerging Roles of Extracellular Vesicles in Cardiac Repair and Rejuvenation

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Emerging Roles of Extracellular Vesicles in Cardiac Repair and Rejuvenation Am J Physiol Heart Circ Physiol 315: H733–H744, 2018. First published June 27, 2018; doi:10.1152/ajpheart.00100.2018. REVIEW Cardiac Regeneration and Repair Emerging roles of extracellular vesicles in cardiac repair and rejuvenation X Faisal J. Alibhai,1 Stephanie W. Tobin,1 Azadeh Yeganeh,1 Richard D. Weisel,1,2 and Ren-Ke Li1,2 1Division of Cardiovascular Surgery, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; and 2Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada Submitted 5 February 2018; accepted in final form 17 June 2018 Alibhai FJ, Tobin SW, Yeganeh A, Weisel RD, Li R-K. Emerging roles of extracellular vesicles in cardiac repair and rejuvenation. Am J Physiol Heart Circ Physiol 315: H733–H744, 2018. First published June 27, 2018; doi:10.1152/ ajpheart.00100.2018.—Cell therapy has received significant attention as a thera- peutic approach to restore cardiac function after myocardial infarction. Accumu- lating evidence supports that beneficial effects observed with cell therapy are due to paracrine secretion of multiple factors from transplanted cells, which alter the tissue microenvironment and orchestrate cardiac repair processes. Of these para- crine factors, extracellular vesicles (EVs) have emerged as a key effector of cell therapy. EVs regulate cellular function through the transfer of cargo, such as microRNAs and proteins, which act on multiple biological pathways within recipient cells. These discoveries have led to the development of cell-free therapies using EVs to improve cardiac repair after a myocardial infarction. Here, we present an overview of the current use of EVs to enhance cardiac repair after myocardial infarction. We also discuss the emerging use of EVs for rejuvenation-based therapies. Finally, future directions for the use of EVs as therapeutic agents for cardiac regenerative medicine are also discussed. aging; cell therapy; extracellular vesicles; myocardial infarction; rejuvenation INTRODUCTION EXTRACELLULAR VESICLES After myocardial infarction (MI), the heart undergoes mal- Classification of EVs adaptive changes in shape and size in a process termed ven- tricular remodeling. The extent of ventricular remodeling di- EV is a broad term referring to membrane-bound vesicles rectly influences the development of cardiac dysfunction and that are released by cells. These vesicles fall into three main 1 2 3 the progression to heart failure. The heart has limited regener- categories: ) exosomes, ) microvesicles, and ) apoptotic bodies. Traditionally, EVs have been classified on the basis of ative capacity; therefore, interventions are needed to prevent size and mode of secretion (Fig. 1). Exosomes are vesicles the loss of contractile elements and enhance endogenous car- ~50–150 nm in size that arise from the endosome and are diac repair to limit detrimental ventricular remodeling. Al- released through multivesicular body (MVB) fusion with the though much attention has been given to cell therapy as a plasma membrane (45). Microvesicles range from ~20 nm to 1 treatment for MI, the therapeutic benefits achieved in clinical ␮m and are formed by direct budding from the cell membrane trials have been limited. This has led a number of research (75). Apoptotic bodies range from ~50 nm to 5 ␮m and are groups to develop new approaches to improve cardiac repair released by blebbing of cells undergoing apoptosis (5). As a post-MI. One promising approach is to supply the factors result of the increasingly recognized complexity and overlap- secreted by transplanted stem cells in a cell-free therapy. ping size ranges of EVs, more stringent classification criteria Extracellular vesicles (EVs) have emerged as key mediators of for EVs have recently been proposed (65, 90). For example, the stem cell function and are currently being studied by many International Society for Extracellular Vesicles has proposed investigators to prevent cardiac dysfunction after a MI. More- that isolated vesicle populations should be characterized using over, there is emerging interest in the use of EVs as mediators a combination of Western blot analysis, flow cytometry, nano- of rejuvenation, whereby EVs restore biological processes in particle tracking analysis, and transmission electron micros- aged individuals to that of a younger state. copy (65). Moreover, protein markers in four categories should be assessed in each vesicle preparation: 1) transmembrane or lipid-bound proteins, 2) cytosolic proteins, 3) intracellular proteins, and 4) extracellular proteins (65). Proper character- Address for reprint requests and other correspondence: R.-K. Li, Univ. Health Network, PMCRT, Rm. 3-702, 101 College St., Toronto, ON, Canada ization of isolated EVs is essential as a change in EV compo- M5G 1L7 (e-mail: [email protected]). sition can impact their therapeutic potential. Although a num- http://www.ajpheart.org 0363-6135/18 Copyright © 2018 the American Physiological Society H733 Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (142.150.190.039) on October 11, 2018. Copyright © 2018 American Physiological Society. All rights reserved. H734 EVs IN CARDIAC REPAIR AND REJUVENATION 2 Microvesicles Fig. 1. Schematic of extracellular vesicle secretion. 1) Sorting of early endosomal cargo in endosomal sorting complex re- quired for transport (ESCRT)-dependent and 1 Exosomes -independent manners leads to the formation of intraluminal vesicles (ILVs) and multive- Early sicular bodies (MVBs). Fusion of MVBs endosome with the lysosome releases ILVs into the compartment, where they are degraded. Fu- MVB sion of MVBs with the plasma membrane leads to the release of ILVs into the extra- cellular space where they are termed exo- somes. 2) In contrast, microvesicles arise ILV from direct budding and pinching from the ESCRT dependent and plasma membrane to release the vesicle into independent sorting the extracellular space. 3) Finally, apoptotic bodies are formed during cell apoptosis as a result of cell blebbing, which releases cellu- lar contents into the extracellular space. Lysosome Degradation 3 Apoptotic body ber of studies have used the term exosome to describe isolated lipid content in secreted EVs (73). Induction of autophagy EVs, no isolation method currently can distinguish exosomes increases fusion of MVBs with autophagosomes, whereas a and microvesicles of similar sizes, and, therefore, the broad reduction in autophagy increases secretion to compensate for term EV is used in this article (35, 57). lysosome dysfunction to dispose of cellular cargo. REGULATION OF EV BIOGENESIS AND SECRETION ESCRT-Independent Regulation Endosomal Sorting Complex Required for Transport- A number of pathways regulate EV biogenesis in an Dependent Regulation ESCRT-independent manner. Neutral sphingomyelinase (N- SMase) controls intraendosomal transport through regula- The endosomal sorting complex required for transport tion of lipid microdomains; inhibition of N-SMase with (ESCRT) comprises more than 30 different proteins that as- GW4869 reduces exosome secretion (99). Rab-GTPases, semble into four complexes (ESCRT-0, ESCRT -I, ESCRT-II, such as Rab27a/b (80) and Rab35 (42), regulate EV secre- and ESCRT-III) and play a major role in regulating EV tion through regulation of vesicle docking to the plasma biogenesis (43). The ESCRT plays an important role in the membrane. Finally, cellular oxygen tension influences EV formation of intraluminal vesicles (ILVs) and MVBs from the biogenesis, as hypoxia increases EV secretion in a hypoxia- endosome (18). ILVs are subsequently released as exosomes inducible factor (HIF)-1␣-dependent manner (34, 105). Col- into the extracellular space after MVB fusion with the plasma lectively, these studies have demonstrated a number of membrane (Fig. 1). Knockdown of ESCRT components tumor cellular pathways that influence EV production through susceptibility gene 101, hepatocyte growth factor receptor ESCRT-dependent and -independent mechanisms. substrate (HRS), or signal transducing adaptor molecule 1 reduces MVB formation and exosome secretion (18). Another EV Cargo mechanism by which ESCRT regulates EV production is through an interaction with the autophagy pathway. Starvation- EVs carry diverse cargo, including mRNAs (101), noncod- induced autophagy reduces EV secretion, as shown using the ing RNAs (14, 15), proteins (33, 46), lipids (40), chromosomal K562 cancer cell line (28). In contrast, blockade of autophagy DNA (94), and mitochondrial DNA (84). In light of this with bafilomycin A1 increases EV secretion in SH-SY5Y diverse cargo, a number of databases have been developed for neuroblastoma cells (6). Mechanistically, the autophagy ma- researchers to search EV cargo. These include ExoCarta (89), chinery and ESCRT components interact to regulate EV bio- Vesiclepedia (46), and EVpedia (52). High-throughput analy- genesis; autophagy related (Atg)12-Atg3 interacts with Alix, ses of EVs have been essential in identifying the factors carried an ESCRT component, to regulate endolysosomal trafficking by EVs. For example, next-generation sequencing studies have (76). These studies support that a balance exists between revealed that EVs carry a diverse set of noncoding RNAs, autophagy and EV secretion. Changes in autophagy flux also including transfer RNAs, Y-RNAs, microRNAs (miRNAs), affect EV composition, as impaired autophagy increases amy- and piRNAs (14, 88). Mass spectrometry studies
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