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      First Characterization of Human Amniotic Fluid Stem Cell Extracellular Vesicles as a Powerful Paracrine Tool Endowed with Regenerative Potential

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          Abstract

          Human amniotic fluid stem cells (hAFS) have shown a distinct secretory profile and significant regenerative potential in several preclinical models of disease. Nevertheless, little is known about the detailed characterization of their secretome. Herein we show for the first time that hAFS actively release extracellular vesicles (EV) endowed with significant paracrine potential and regenerative effect. c‐KIT + hAFS were isolated from leftover samples of amniotic fluid from prenatal screening and stimulated to enhance EV release (24 hours 20% O 2 versus 1% O 2 preconditioning). The capacity of the c‐KIT + hAFS‐derived EV (hAFS‐EV) to induce proliferation, survival, immunomodulation, and angiogenesis were investigated in vitro and in vivo. The hAFS‐EV regenerative potential was also assessed in a model of skeletal muscle atrophy ( HSA‐Cre, Smn F7/F7 mice), in which mouse AFS transplantation was previously shown to enhance muscle strength and survival. hAFS secreted EV ranged from 50 up to 1,000 nm in size. In vitro analysis defined their role as biological mediators of regenerative, paracrine effects while their modulatory role in decreasing skeletal muscle inflammation in vivo was shown for the first time. Hypoxic preconditioning significantly induced the enrichment of exosomes endowed with regenerative microRNAs within the hAFS‐EV. In conclusion, this is the first study showing that c‐KIT + hAFS dynamically release EV endowed with remarkable paracrine potential, thus representing an appealing tool for future regenerative therapy. S tem C ells T ranslational M edicine 2017;6:1340–1355

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          ExoCarta: A Web-Based Compendium of Exosomal Cargo.

          Exosomes are membranous vesicles that are released by a variety of cells into the extracellular microenvironment and are implicated in intercellular communication. As exosomes contain RNA, proteins and lipids, there is a significant interest in characterizing the molecular cargo of exosomes. Here, we describe ExoCarta (http://www.exocarta.org), a manually curated Web-based compendium of exosomal proteins, RNAs and lipids. Since its inception, the database has been highly accessed (>54,000 visitors from 135 countries). The current version of ExoCarta hosts 41,860 proteins, >7540 RNA and 1116 lipid molecules from more than 286 exosomal studies annotated with International Society for Extracellular Vesicles minimal experimental requirements for definition of extracellular vesicles. Besides, ExoCarta features dynamic protein-protein interaction networks and biological pathways of exosomal proteins. Users can download most often identified exosomal proteins based on the number of studies. The downloaded files can further be imported directly into FunRich (http://www.funrich.org) tool for additional functional enrichment and interaction network analysis.
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            Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth.

            Multipotent mesenchymal stromal cells (MSCs) have potential therapeutic benefit for the treatment of neurological diseases and injury. MSCs interact with and alter brain parenchymal cells by direct cell-cell communication and/or by indirect secretion of factors and thereby promote functional recovery. In this study, we found that MSC treatment of rats subjected to middle cerebral artery occlusion (MCAo) significantly increased microRNA 133b (miR-133b) level in the ipsilateral hemisphere. In vitro, miR-133b levels in MSCs and in their exosomes increased after MSCs were exposed to ipsilateral ischemic tissue extracts from rats subjected to MCAo. miR-133b levels were also increased in primary cultured neurons and astrocytes treated with the exosome-enriched fractions released from these MSCs. Knockdown of miR-133b in MSCs confirmed that the increased miR-133b level in astrocytes is attributed to their transfer from MSCs. Further verification of this exosome-mediated intercellular communication was performed using a cel-miR-67 luciferase reporter system and an MSC-astrocyte coculture model. Cel-miR-67 in MSCs was transferred to astrocytes via exosomes between 50 and 100 nm in diameter. Our data suggest that the cel-miR-67 released from MSCs was primarily contained in exosomes. A gap junction intercellular communication inhibitor arrested the exosomal microRNA communication by inhibiting exosome release. Cultured neurons treated with exosome-enriched fractions from MSCs exposed to 72 hours post-MCAo brain extracts significantly increased the neurite branch number and total neurite length. This study provides the first demonstration that MSCs communicate with brain parenchymal cells and may regulate neurite outgrowth by transfer of miR-133b to neural cells via exosomes. Copyright © 2012 AlphaMed Press.
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              Regulatory interactions between muscle and the immune system during muscle regeneration.

              Recent discoveries reveal complex interactions between skeletal muscle and the immune system that regulate muscle regeneration. In this review, we evaluate evidence that indicates that the response of myeloid cells to muscle injury promotes muscle regeneration and growth. Acute perturbations of muscle activate a sequence of interactions between muscle and inflammatory cells. The initial inflammatory response is a characteristic Th1 inflammatory response, first dominated by neutrophils and subsequently by CD68(+) M1 macrophages. M1 macrophages can propagate the Th1 response by releasing proinflammatory cytokines and cause further tissue damage through the release of nitric oxide. Myeloid cells in the early Th1 response stimulate the proliferative phase of myogenesis through mechanisms mediated by TNF-alpha and IL-6; experimental prolongation of their presence is associated with delayed transition to the early differentiation stage of myogenesis. Subsequent invasion by CD163(+)/CD206(+) M2 macrophages attenuates M1 populations through the release of anti-inflammatory cytokines, including IL-10. M2 macrophages play a major role in promoting growth and regeneration; their absence greatly slows muscle growth following injury or modified use and inhibits muscle differentiation and regeneration. Chronic muscle injury leads to profiles of macrophage invasion and function that differ from acute injuries. For example, mdx muscular dystrophy yields invasion of muscle by M1 macrophages, but their early invasion is accompanied by a subpopulation of M2a macrophages. M2a macrophages are IL-4 receptor(+)/CD206(+) cells that reduce cytotoxicity of M1 macrophages. Subsequent invasion of dystrophic muscle by M2c macrophages is associated with progression of the regenerative phase in pathophysiology. Together, these findings show that transitions in macrophage phenotype are an essential component of muscle regeneration in vivo following acute or chronic muscle damage.
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                Author and article information

                Contributors
                sveva.bollini@unige.it
                Journal
                Stem Cells Transl Med
                Stem Cells Transl Med
                10.1002/(ISSN)2157-6580
                SCT3
                Stem Cells Translational Medicine
                John Wiley and Sons Inc. (Hoboken )
                2157-6564
                2157-6580
                08 March 2017
                May 2017
                : 6
                : 5 ( doiID: 10.1002/sct3.2017.6.issue-5 )
                : 1340-1355
                Affiliations
                [ 1 ] Regenerative Medicine Laboratory, Department of Experimental MedicineUniversity of Genova GenovaItaly
                [ 2 ] Stem Cells and Regenerative Medicine LaboratoryFondazione Istituto di Ricerca Pediatrica Città della Speranza PadovaItaly
                [ 3 ] Laboratory of Molecular and Cellular CardiologyCardioCentro Ticino Foundation_CCT Lugano Switzerland
                [ 4 ] Drug Discovery and Development DepartmentIIT‐Fondazione Istituto Italiano di Tecnologia GenovaItaly
                [ 5 ]Molecular Pathology Unit, IRCCS AOU San Martino ‐ IST National Institute for Cancer Research GenovaItaly
                [ 6 ] Veterinary Medicine DepartmentUniversity of Perugia PerugiaItaly
                [ 7 ] Molecular Biology LaboratoryIRCCS Istituto Giannina Gaslini GenovaItaly
                [ 8 ] Human Genetics LaboratoryE.O. Ospedali Galliera GenovaItaly
                [ 9 ] Department of Woman and Child HealthUniversity of Padova PadovaItaly
                Author notes
                [*] [* ]Correspondence: Sveva Bollini, Ph.D., Department of Experimental Medicine, University of Genova, 16132 L.go R. Benzi 10, Genova, Italy. Telephone: +39 010 5558394; Fax: +39 010 5558247; e‐mail: sveva.bollini@ 123456unige.it
                Article
                SCT312132
                10.1002/sctm.16-0297
                5442724
                28271621
                30502a6e-bf83-4510-9895-41bc4073a454
                © 2017 The Authors S tem C ells T ranslational M edicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 20 June 2016
                : 08 November 2016
                : 21 December 2016
                Page count
                Figures: 6, Tables: 0, Pages: 16, Words: 11747
                Categories
                Fetal and Neonatal Stem Cells
                Translational Research Articles and Reviews
                Fetal and Neonatal Stem Cells
                Custom metadata
                2.0
                sct312132
                May 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.9 mode:remove_FC converted:23.05.2017

                fetal stem cells,paracrine communication,extracellular vesicles,exosomes,proliferation,apoptosis,mirna,tissue regeneration

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