title: Mesenchymal Stem Cell-Derived Extracellular Vesicles as Mediators of Anti-Inflammatory Effects: Endorsement of Macrophage Polarization.
abstract: Mesenchymal Stem Cells (MSCs) are effective therapeutic agents enhancing the repair of injured tissues mostly through their paracrine activity. Increasing evidences show that besides the secretion of soluble molecules, the release of extracellular vesicles (EVs) represents an alternative mechanism adopted by MSCs. Since macrophages are essential contributors toward the resolution of inflammation, which has emerged as a finely orchestrated process, the aim of the present study was to carry out a detailed characterization of EVs released by human adipose derived-MSCs to investigate their involvement as modulators of MSC anti-inflammatory effects inducing macrophage polarization. The EV-isolation method was based on repeated ultracentrifugations of the medium conditioned by MSC exposed to normoxic or hypoxic conditions (EVNormoand EVHypo). Both types of EVs were efficiently internalized by responding bone marrow-derived macrophages, eliciting their switch from a M1 to a M2 phenotype. In vivo, following cardiotoxin-induced skeletal muscle damage, EVNormoand EVHypointeracted with macrophages recruited during the initial inflammatory response. In injured and EV-treated muscles, a downregulation of IL6 and the early marker of innate and classical activation Nos2 were concurrent to a significant upregulation of Arg1 and Ym1, late markers of alternative activation, as well as an increased percentage of infiltrating CD206poscells. These effects, accompanied by an accelerated expression of the myogenic markers Pax7, MyoD, and eMyhc, were even greater following EVHypoadministration. Collectively, these data indicate that MSC-EVs possess effective anti-inflammatory properties, making them potential therapeutic agents more handy and safe than MSCs. Stem Cells Translational Medicine 2017 Stem Cells Translational Medicine 2017;6:1018-1028.
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova, Italy.|U.O. Regenerative Medicine, IRCCS AOU San Martino-IST, National Cancer Research Institute, Genova, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lo Sicco
authors.affiliation: U.O. Molecular Pathology, IRCCS AOU San Martino-IST, National Cancer Research Institute, Genova, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Reverberi
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Balbi
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Ulivi
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Principi
authors.affiliation: Department of Veterinary Medicine, University of Perugia, Perugia, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Pascucci
authors.affiliation: Molecular Biology Laboratory, Istituto Giannina Gaslini, Genova, Italy.|Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Becherini
authors.affiliation: Molecular Biology Laboratory, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Maria Carla
authors.initials: MC
authors.lastname: Bosco
authors.affiliation: Molecular Biology Laboratory, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Varesio
authors.affiliation: Stem Cells and Regenerative Medicine Lab, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Franzin
authors.affiliation: Stem Cells and Regenerative Medicine Lab, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy.|Department of Women and Children Health, University of Padova, Padova, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Pozzobon
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Ranieri
authors.initials: R
authors.lastname: Cancedda
authors.affiliation: U.O. Regenerative Medicine, IRCCS AOU San Martino-IST, National Cancer Research Institute, Genova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Tasso
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000067128:Extracellular Vesicles / Q000378:metabolism*; D005434:Flow Cytometry; D007249:Inflammation / Q000378:metabolism / Q000628:therapy; D008264:Macrophages / Q000378:metabolism* / Q000502:physiology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000893:Anti-Inflammatory Agents
keywords: Cell hypoxia; Extracellular vesicles; Inflammation; Macrophages; Mesenchymal stem cells; Regenerative medicine