title: Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension.
abstract: BACKGROUND
  Hypoxia induces an inflammatory response in the lung manifested by alternative activation of macrophages with elevation of proinflammatory mediators that are critical for the later development of hypoxic pulmonary hypertension. Mesenchymal stromal cell transplantation inhibits lung inflammation, vascular remodeling, and right heart failure and reverses hypoxic pulmonary hypertension in experimental models of disease. In this study, we aimed to investigate the paracrine mechanisms by which mesenchymal stromal cells are protective in hypoxic pulmonary hypertension.
  
  
  RESULTS
  We fractionated mouse mesenchymal stromal cell-conditioned media to identify the biologically active component affecting in vivo hypoxic signaling and determined that exosomes, secreted membrane microvesicles, suppressed the hypoxic pulmonary influx of macrophages and the induction of proinflammatory and proproliferative mediators, including monocyte chemoattractant protein-1 and hypoxia-inducible mitogenic factor, in the murine model of hypoxic pulmonary hypertension. Intravenous delivery of mesenchymal stromal cell-derived exosomes (MEX) inhibited vascular remodeling and hypoxic pulmonary hypertension, whereas MEX-depleted media or fibroblast-derived exosomes had no effect. MEX suppressed the hypoxic activation of signal transducer and activator of transcription 3 (STAT3) and the upregulation of the miR-17 superfamily of microRNA clusters, whereas it increased lung levels of miR-204, a key microRNA, the expression of which is decreased in human pulmonary hypertension. MEX produced by human umbilical cord mesenchymal stromal cells inhibited STAT3 signaling in isolated human pulmonary artery endothelial cells, demonstrating a direct effect of MEX on hypoxic vascular cells.
  
  
  CONCLUSIONS
  This study indicates that MEX exert a pleiotropic protective effect on the lung and inhibit pulmonary hypertension through suppression of hyperproliferative pathways, including STAT3-mediated signaling induced by hypoxia.
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA.
authors.forename: Changjin
authors.initials: C
authors.lastname: Lee
authors.forename: S Alex
authors.initials: SA
authors.lastname: Mitsialis
authors.forename: Muhammad
authors.initials: M
authors.lastname: Aslam
authors.forename: Sally H
authors.initials: SH
authors.lastname: Vitali
authors.forename: Eleni
authors.initials: E
authors.lastname: Vergadi
authors.forename: Georgios
authors.initials: G
authors.lastname: Konstantinou
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Sdrimas
authors.forename: Angeles
authors.initials: A
authors.lastname: Fernandez-Gonzalez
authors.forename: Stella
authors.initials: S
authors.lastname: Kourembanas
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D055354:Exosomes / Q000378:metabolism / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D000860:Hypoxia / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D019899:Paracrine Communication / Q000502:physiology; D011014:Pneumonia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D050796:STAT3 Transcription Factor / Q000378:metabolism; D059631:Wharton Jelly / Q000166:cytology
chemical_list: D017077:Culture Media, Conditioned; C524941:MIRN17 microRNA, human; C549404:MIRN204 microRNA, human; C574692:MIRN204 microRNA, mouse; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse