title: Therapeutic Effects of Human Mesenchymal Stem Cell-derived Microvesicles in Severe Pneumonia in Mice.
abstract: BACKGROUND
  Microvesicles (MVs) are anuclear fragments of cells released from the endosomal compartment or shed from surface membranes. We and other investigators demonstrated that MVs released by mesenchymal stem cells (MSCs) were as effective as the cells themselves in inflammatory injuries, such as after endotoxin-induced acute lung injury. However, the therapeutic effects of MVs in an infectious model of acute lung injury remain unknown.
  
  
  OBJECTIVE
  We investigated the effects of human MSC MVs on lung inflammation, protein permeability, bacterial clearance, and survival after severe bacterial pneumonia.
  
  
  METHODS
  We tested the effects of MVs derived from human MSCs on Escherichia coli pneumonia in mice. We also studied the interactions between MVs and human monocytes and human alveolar epithelial type 2 cells.
  
  
  RESULTS
  Administration of MVs derived from human MSCs improved survival in part through keratinocyte growth factor secretion and decreased the influx of inflammatory cells, cytokines, protein, and bacteria in mice injured with bacterial pneumonia. In primary cultures of human monocytes or alveolar type 2 cells, the uptake of MVs was mediated by CD44 receptors, which were essential for the therapeutic effects. MVs enhanced monocyte phagocytosis of bacteria while decreasing inflammatory cytokine secretion and increased intracellular ATP levels in injured alveolar epithelial type 2 cells. Prestimulation of MSCs with a toll-like receptor 3 agonist further enhanced the therapeutic effects of the released MVs.
  
  
  CONCLUSIONS
  MVs derived from human MSCs were as effective as the parent stem cells in severe bacterial pneumonia.
authors.affiliation: 1 Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, University Pierre and Maris Curie (UPMC) Univ Paris 06, Paris, France.|2 Department of Immunology-Immunopathology-Biotherapy UPMC Univ Paris 06, Sorbonne Universités, INSERM UMRS 959, Paris, France; and.|3 Department of Anesthesiology & Medicine, University of California San Francisco, San Francisco, California.
authors.forename: Antoine
authors.initials: A
authors.lastname: Monsel
authors.affiliation: 3 Department of Anesthesiology & Medicine, University of California San Francisco, San Francisco, California.
authors.forename: Ying-gang
authors.initials: YG
authors.lastname: Zhu
authors.affiliation: 3 Department of Anesthesiology & Medicine, University of California San Francisco, San Francisco, California.
authors.forename: Stephane
authors.initials: S
authors.lastname: Gennai
authors.affiliation: 3 Department of Anesthesiology & Medicine, University of California San Francisco, San Francisco, California.
authors.forename: Qi
authors.initials: Q
authors.lastname: Hao
authors.affiliation: 3 Department of Anesthesiology & Medicine, University of California San Francisco, San Francisco, California.
authors.forename: Shuling
authors.initials: S
authors.lastname: Hu
authors.affiliation: 1 Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, University Pierre and Maris Curie (UPMC) Univ Paris 06, Paris, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Rouby
authors.affiliation: 2 Department of Immunology-Immunopathology-Biotherapy UPMC Univ Paris 06, Sorbonne Universités, INSERM UMRS 959, Paris, France; and.
authors.forename: Michelle
authors.initials: M
authors.lastname: Rosenzwajg
authors.affiliation: 3 Department of Anesthesiology & Medicine, University of California San Francisco, San Francisco, California.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: 3 Department of Anesthesiology & Medicine, University of California San Francisco, San Francisco, California.
authors.forename: Jae W
authors.initials: JW
authors.lastname: Lee
mesh_terms: D055371:Acute Lung Injury / Q000382:microbiology / Q000628:therapy*; D000818:Animals; D055252:Cell-Derived Microparticles / Q000637:transplantation*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018410:Pneumonia, Bacterial / Q000628:therapy*
keywords: acute respiratory distress syndrome; bacterial pneumonia; mesenchymal stem cells; microvesicles