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      Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way

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          Abstract

          <p class="first" id="P1">Hypoxia treatment enhances paracrine effect of mesenchymal stem cells (MSCs). The aim of this study was to investigate whether exosomes from hypoxia-treated MSCs (Exo <sup>H</sup>) are superior to those from normoxia-treated MSCs (Exo <sup>N</sup>) for myocardial repair. Mouse bone marrow-derived MSCs were cultured under hypoxia or normoxia for 24 h, and exosomes from conditioned media were intramyocardially injected into infarcted heart of C57BL/6 mouse. Exo <sup>H</sup> resulted in significantly higher survival, smaller scar size and better cardiac functions recovery. Exo <sup>H</sup> conferred increased vascular density, lower cardiomyocytes (CMs) apoptosis, reduced fibrosis and increased recruitment of cardiac progenitor cells in the infarcted heart relative to Exo <sup>N</sup>. MicroRNA analysis revealed significantly higher levels of microRNA-210 (miR-210) in Exo <sup>H</sup> compared with Exo <sup>N</sup>. Transfection of a miR-210 mimic into endothelial cells (ECs) and CMs conferred similar biological effects as Exo <sup>H</sup>. Hypoxia treatment of MSCs increased the expression of neutral sphingomyelinase 2 (nSMase2) which is crucial for exosome secretion. Blocking the activity of nSMase2 resulted in reduced miR-210 secretion and abrogated the beneficial effects of Exo <sup>H</sup>. In conclusion, hypoxic culture augments miR-210 and nSMase2 activities in MSCs and their secreted exosomes, and this is responsible at least in part for the enhanced cardioprotective actions of exosomes derived from hypoxia-treated cells. </p>

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          Most cited references 18

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          Biogenesis and secretion of exosomes.

          Although observed for several decades, the release of membrane-enclosed vesicles by cells into their surrounding environment has been the subject of increasing interest in the past few years, which led to the creation, in 2012, of a scientific society dedicated to the subject: the International Society for Extracellular Vesicles. Convincing evidence that vesicles allow exchange of complex information fuelled this rise in interest. But it has also become clear that different types of secreted vesicles co-exist, with different intracellular origins and modes of formation, and thus probably different compositions and functions. Exosomes are one sub-type of secreted vesicles. They form inside eukaryotic cells in multivesicular compartments, and are secreted when these compartments fuse with the plasma membrane. Interestingly, different families of molecules have been shown to allow intracellular formation of exosomes and their subsequent secretion, which suggests that even among exosomes different sub-types exist. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3.

            MicroRNAs (miRNAs) are small non-protein-coding RNAs that function as negative gene expression regulators. In the present study, we investigated miRNAs role in endothelial cell response to hypoxia. We found that the expression of miR-210 progressively increased upon exposure to hypoxia. miR-210 overexpression in normoxic endothelial cells stimulated the formation of capillary-like structures on Matrigel and vascular endothelial growth factor-driven cell migration. Conversely, miR-210 blockade via anti-miRNA transfection inhibited the formation of capillary-like structures stimulated by hypoxia and decreased cell migration in response to vascular endothelial growth factor. miR-210 overexpression did not affect endothelial cell growth in both normoxia and hypoxia. However, anti-miR-210 transfection inhibited cell growth and induced apoptosis, in both normoxia and hypoxia. We determined that one relevant target of miR-210 in hypoxia was Ephrin-A3 since miR-210 was necessary and sufficient to down-modulate its expression. Moreover, luciferase reporter assays showed that Ephrin-A3 was a direct target of miR-210. Ephrin-A3 modulation by miR-210 had significant functional consequences; indeed, the expression of an Ephrin-A3 allele that is not targeted by miR-210 prevented miR-210-mediated stimulation of both tubulogenesis and chemotaxis. We conclude that miR-210 up-regulation is a crucial element of endothelial cell response to hypoxia, affecting cell survival, migration, and differentiation.
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              Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis.

              Extracellular vesicles such as exosomes and microvesicles (MVs) are shed by cancer cells, are detected in the plasma of cancer patients, and promote cancer progression, but the molecular mechanisms regulating their production are not well understood. Intratumoral hypoxia is common in advanced breast cancers and is associated with an increased risk of metastasis and patient mortality that is mediated in part by the activation of hypoxia-inducible factors (HIFs). In this paper, we report that exposure of human breast cancer cells to hypoxia augments MV shedding that is mediated by the HIF-dependent expression of the small GTPase RAB22A, which colocalizes with budding MVs at the cell surface. Incubation of naïve breast cancer cells with MVs shed by hypoxic breast cancer cells promotes focal adhesion formation, invasion, and metastasis. In breast cancer patients, RAB22A mRNA overexpression in the primary tumor is associated with decreased overall and metastasis-free survival and, in an orthotopic mouse model, RAB22A knockdown impairs breast cancer metastasis.
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                Author and article information

                Journal
                Artificial Cells, Nanomedicine, and Biotechnology
                Artificial Cells, Nanomedicine, and Biotechnology
                Informa UK Limited
                2169-1401
                2169-141X
                November 16 2017
                November 16 2017
                : 1-12
                Affiliations
                [1 ] Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China;
                [2 ] Department of Cardiology, Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, PR China;
                [3 ] Department of Cardiology, The First People’s Hospital of Huzhou, Huzhou, PR China;
                [4 ] Vascular Biology Center, Department of Medicine, Medical College of Georgia/Georgia Regents University, Augusta, GA, USA;
                [5 ] Department of Molecular and Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
                Article
                10.1080/21691401.2017.1388249
                5955787
                29141446
                © 2017

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