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      Exosomes in Mesenchymal Stem Cells, a New Therapeutic Strategy for Cardiovascular Diseases?

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          Abstract

          Cardiovascular diseases (CVDs) are still a major cause of people deaths worldwide, and mesenchymal stem cells (MSCs) transplantation holds great promise due to its capacity to differentiate into cardiovascular cells and secrete protective cytokines, which presents an important mechanism of MSCs therapy for CVDs. Although the capability of MSCs to differentiate into cardiomyocytes (CMCs), endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) has been well recognized in massive previous experiments both in vitro and in vivo, low survival rate of transplanted MSCs in recipient hearts suggests that therapeutic effects of MSCs transplantation might be also correlated with other underlying mechanisms. Notably, recent studies uncovered that MSCs were able to secret cholesterol-rich, phospholipid exosomes which were enriched with microRNAs (miRNAs). The released exosomes from MSCs acted on hearts and vessels, and then exerted anti-apoptosis, cardiac regeneration, anti-cardiac remodeling, anti-inflammatory effects, neovascularization and anti-vascular remodeling, which are considered as novel molecular mechanisms of therapeutic potential of MSCs transplantation. Here we summarized recent advances about the role of exosomes in MSCs therapy for CVDs, and discussed exosomes as a novel approach in the treatment of CVDs in the future.

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          Most cited references70

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          Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.

          Severe acute renal failure (ARF) remains a common, largely treatment-resistant clinical problem with disturbingly high mortality rates. Therefore, we tested whether administration of multipotent mesenchymal stem cells (MSC) to anesthetized rats with ischemia-reperfusion-induced ARF (40-min bilateral renal pedicle clamping) could improve the outcome through amelioration of inflammatory, vascular, and apoptotic/necrotic manifestations of ischemic kidney injury. Accordingly, intracarotid administration of MSC (approximately 10(6)/animal) either immediately or 24 h after renal ischemia resulted in significantly improved renal function, higher proliferative and lower apoptotic indexes, as well as lower renal injury and unchanged leukocyte infiltration scores. Such renoprotection was not obtained with syngeneic fibroblasts. Using in vivo two-photon laser confocal microscopy, fluorescence-labeled MSC were detected early after injection in glomeruli, and low numbers attached at microvasculature sites. However, within 3 days of administration, none of the administered MSC had differentiated into a tubular or endothelial cell phenotype. At 24 h after injury, expression of proinflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma, and inducible nitric oxide synthase was significantly reduced and that of anti-inflammatory IL-10 and bFGF, TGF-alpha, and Bcl-2 was highly upregulated in treated kidneys. We conclude that the early, highly significant renoprotection obtained with MSC is of considerable therapeutic promise for the cell-based management of clinical ARF. The beneficial effects of MSC are primarily mediated via complex paracrine actions and not by their differentiation into target cells, which, as such, appears to be a more protracted response that may become important in late-stage organ repair.
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            Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease.

            Cardiovascular disease is a major target for many experimental stem cell-based therapies and mesenchymal stem cells (MSCs) are widely used in these therapies. Transplantation of MSCs to treat cardiac disease has always been predicated on the hypothesis that these cells would engraft, differentiate and replace damaged cardiac tissues. However, experimental or clinical observations so far have failed to demonstrate a therapeutically relevant level of transplanted MSC engraftment or differentiation. Instead, they indicate that transplanted MSCs secrete factors to reduce tissue injury and/or enhance tissue repair. Here we review the evidences supporting this hypothesis including the recent identification of exosome as a therapeutic agent in MSC secretion. In particular, we will discuss the potential and practicality of using this relatively novel entity as a therapeutic modality for the treatment of cardiac disease, particularly acute myocardial infarction.
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              Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo.

              Mesenchymal stem cells (MSCs) can promote tumor growth in a mouse xenograft model, but the exact mechanism remains unclear. In this study, we investigated the effects of bone marrow MSC-derived exosomes (MSC-exosomes) on tumor growth in vitro and in vivo. Our results showed that MSC-exosomes promoted tumor growth in vivo. MSC-exosomes enhanced vascular endothelial growth factor (VEGF) expression in tumor cells by activating extracellular signal-regulated kinase1/2 (ERK1/2) pathway. Inhibition of ERK1/2 activation reserved the increase of VEGF level by MSC-exosomes. Our findings demonstrate a new mechanism through which MSC-exosome-mediated cell-cell interactions may contribute to tumor progression. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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                Author and article information

                Journal
                Int J Biol Sci
                Int. J. Biol. Sci
                ijbs
                International Journal of Biological Sciences
                Ivyspring International Publisher (Sydney )
                1449-2288
                2015
                12 January 2015
                : 11
                : 2
                : 238-245
                Affiliations
                Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin 150081, China.
                Author notes
                ✉ Corresponding author: Dr. Benzhi Cai, Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, 157# Baojian Road, Nangang District, Harbin 150081, Heilongjiang, China; Tel.: +86 451 8666-9473; Fax: +86 451 8667-1354; Email: caibz@ 123456ems.hrbmu.edu.cn

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                ijbsv11p0238
                10.7150/ijbs.10725
                4308409
                25632267
                2ff578a4-1a1a-414e-83fe-afe01dd68732
                © 2015 Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. Please see http://ivyspring.com/terms for terms and conditions.
                History
                : 4 October 2014
                : 9 December 2014
                Categories
                Review

                Life sciences
                microrna,exosomes,mesenchymal stem cell,myocardial infarction,reperfusion injury,pulmonary hypertension

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