title: Mesenchymal stem cells attenuate inflammatory processes in the heart and lung via inhibition of TNF signaling.
abstract: Mesenchymal stem cells (MSC) have been used to treat different clinical conditions although the mechanisms by which pathogenetic processes are affected are still poorly understood. We have previously analyzed the homing of bone marrow-derived MSC to diseased tissues characterized by a high degree of mononuclear cell infiltration and postulated that MSC might modulate inflammatory responses. Here, we demonstrate that MSC mitigate adverse tissue remodeling, improve organ function, and extend lifespan in a mouse model of inflammatory dilative cardiomyopathy (DCM). Furthermore, MSC attenuate Lipopolysaccharide-induced acute lung injury indicating a general role in the suppression of inflammatory processes. We found that MSC released sTNF-RI, which suppressed activation of the NFκBp65 pathway in cardiomyocytes during DCM in vivo. Substitution of MSC by recombinant soluble TNF-R partially recapitulated the beneficial effects of MSC while knockdown of TNF-R prevented MSC-mediated suppression of the NFκBp65 pathway and improvement of tissue pathology. We conclude that sTNF-RI is a major part of the paracrine machinery by which MSC effect local inflammatory reactions.
authors.affiliation: Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Martire
authors.affiliation: Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany.
authors.forename: Fikru B
authors.initials: FB
authors.lastname: Bedada
authors.affiliation: Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Uchida
authors.affiliation: Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany.|Department of Cardiac Surgery, Schüchtermann-Klinik, Ulmenallee 11, 49214, Bad Rothenfelde, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Pöling
authors.affiliation: Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.affiliation: Institute for Heart and Circulation Research, University of Witten/Herdecke, Alfred-Herrhausen-Straße 50, 58448, Witten, Germany.|Department of Cardiac Surgery, Schüchtermann-Klinik, Ulmenallee 11, 49214, Bad Rothenfelde, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Warnecke
authors.affiliation: Department of Cardiac Surgery, Kerckhoff-Clinic, Benekestrasse 2-8, 61231, Bad Nauheim, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Richter
authors.affiliation: Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kubin
authors.affiliation: Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center, Klinikstr. 33, 35392, Giessen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.affiliation: Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany. Thomas.Braun@mpi-bn.mpg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000276:immunology* / Q000473:pathology*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006321:Heart; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D013058:Mass Spectrometry; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha
keywords: Acute lung injury; Fibrosis; Heart failure; Inflammation; Mesenchymal stem cells; Proteomics; TNF-α