title: Prospectively defined murine mesenchymal stem cells inhibit Klebsiella pneumoniae-induced acute lung injury and improve pneumonia survival.
abstract: BACKGROUND
  Numerous studies have described the immunosuppressive capacity of mesenchymal stem cells (MSC) but these studies use mixtures of heterogeneous progenitor cells for in vitro expansion. Recently, multipotent MSC have been prospectively identified in murine bone marrow (BM) on the basis of PDFGRa(+) SCA1(+) CD45(-) TER119(-) (PαS) expression but the immunomodulatory capacity of these MSC is unknown.
  
  
  METHODS
  We isolated PαS MSC by high-purity FACS sorting of murine BM and after in vitro expansion we analyzed the in vivo immunomodulatory activity during acute pneumonia. PαS MSC (1 × 10(6)) were applied intratracheally 4 h after acute respiratory Klebsiella pneumoniae induced infection.
  
  
  RESULTS
  PαS MSC treatment resulted in significantly reduced alveolitis and protein leakage in comparison to mock-treated controls. PαS MSC-treated mice exhibited significantly reduced alveolar TNF-α and IL-12p70 expression, while IL-10 expression was unaffected. Dissection of respiratory dendritic cell (DC) subsets by multiparameter flow cytometry revealed significantly reduced lung DC infiltration and significantly reduced CD86 costimulatory expression on lung CD103(+) DC in PαS MSC-treated mice. In the post-acute phase of pneumonia, PαS MSC-treated animals exhibited significantly reduced respiratory IL-17(+) CD4(+) T cells and IFN-γ(+) CD4(+) T cells. Moreover, PαS MSC treatment significantly improved overall pneumonia survival and did not increase bacterial load.
  
  
  CONCLUSIONS
  In this study we demonstrated for the first time the feasibility and in vivo immunomodulatory capacity of prospectively defined MSC in pneumonia.
authors.affiliation: Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), University Hospital Giessen und Marburg, Justus-Liebig-University Giessen, Langhansstr. 7, D-35390, Giessen, Germany. Holger.Hackstein@immunologie.med.uni-giessen.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Hackstein
authors.affiliation: Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), University Hospital Giessen und Marburg, Justus-Liebig-University Giessen, Langhansstr. 7, D-35390, Giessen, Germany. Anne.Lippitsch@immunologie.med.uni-giessen.de.
authors.forename: Anne
authors.initials: A
authors.lastname: Lippitsch
authors.affiliation: Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), University Hospital Giessen und Marburg, Justus-Liebig-University Giessen, Langhansstr. 7, D-35390, Giessen, Germany. Philippkrug@gmx.net.
authors.forename: Philipp
authors.initials: P
authors.lastname: Krug
authors.affiliation: Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), University Hospital Giessen und Marburg, Justus-Liebig-University Giessen, Langhansstr. 7, D-35390, Giessen, Germany. Inna.schev@web.de.
authors.forename: Inna
authors.initials: I
authors.lastname: Schevtschenko
authors.affiliation: Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), University Hospital Giessen und Marburg, Justus-Liebig-University Giessen, Langhansstr. 7, D-35390, Giessen, Germany. Sabine.kranz@uni-wuerzburg.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kranz
authors.affiliation: Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), University Hospital Giessen und Marburg, Justus-Liebig-University Giessen, Giessen, Germany. Matthias.Hecker@innere.med.uni-giessen.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hecker
authors.affiliation: Department of Veterinary Pathology, Freie Universität Berlin, Robert-von-Ostertag-Str. 15, 14163, Berlin, Germany. Kristina.Dietert@fu-berlin.de.
authors.forename: Kristina
authors.initials: K
authors.lastname: Dietert
authors.affiliation: Department of Veterinary Pathology, Freie Universität Berlin, Robert-von-Ostertag-Str. 15, 14163, Berlin, Germany. Achim.gruber@fu-berlin.de.
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
authors.affiliation: Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), University Hospital Giessen und Marburg, Justus-Liebig-University Giessen, Langhansstr. 7, D-35390, Giessen, Germany. Gregor.Bein@immunologie.med.uni-giessen.de.
authors.forename: Gregor
authors.initials: G
authors.lastname: Bein
authors.affiliation: Department of Hematology, Oncology and Immunology, Philipps University Marburg, University Hospital Giessen und Marburg, Marburg, Germany. Brendelc@staff.uni-marburg.de.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Brendel
authors.affiliation: Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), University Hospital Giessen und Marburg, Justus-Liebig-University Giessen, Langhansstr. 7, D-35390, Giessen, Germany. Nelli.Baal@immunologie.med.uni-giessen.de.
authors.forename: Nelli
authors.initials: N
authors.lastname: Baal
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005434:Flow Cytometry; D018836:Inflammation Mediators / Q000378:metabolism; D007710:Klebsiella Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000601:surgery*; D007711:Klebsiella pneumoniae / Q000276:immunology* / Q000472:pathogenicity; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010641:Phenotype; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000601:surgery*; D013997:Time Factors
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators