Suppression of Neutrophil-Mediated Tissue Damage-A Novel Skill of Mesenchymal Stem Cells.
Mesenchymal stem cells (MSCs) are crucial for tissue homeostasis and regeneration. Though of prime interest, their potentially protective role on neutrophil-induced tissue damage, associated with high morbidity and mortality, has not been explored in sufficient detail. Here we report the therapeutic skill of MSCs to suppress unrestrained neutrophil activation and to attenuate severe tissue damage in a murine immune-complex mediated vasculitis model of unbalanced neutrophil activation. MSC-mediated neutrophil suppression was due to intercellular adhesion molecule 1-dependent engulfment of neutrophils by MSCs, decreasing overall neutrophil numbers. Similar to MSCs in their endogenous niche of murine and human vasculitis, therapeutically injected MSCs via upregulation of the extracellular superoxide dismutase (SOD3), reduced superoxide anion concentrations and consequently prevented neutrophil death, neutrophil extracellular trap formation and spillage of matrix degrading neutrophil elastase, gelatinase and myeloperoxidase. SOD3-silenced MSCs did not exert tissue protective effects. Thus, MSCs hold substantial therapeutic promise to counteract tissue damage in conditions with unrestrained neutrophil activation. Stem Cells 2016;34:2393-2406.
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Dongsheng
D
Jiang
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Jana
J
Muschhammer
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Yu
Y
Qi
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Andrea
A
Kügler
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Juliane C
JC
de Vries
Department of Biochemistry, School of Medicine, Justus-Liebig-University of Giessen, Giessen, Germany.
Mona
M
Saffarzadeh
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Anca
A
Sindrilaru
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Seppe Vander
SV
Beken
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Meinhard
M
Wlaschek
Ticeba GmbH, Heidelberg, Germany.
Mark A
MA
Kluth
Ticeba GmbH, Heidelberg, Germany.
Christoph
C
Ganss
Department of Medicine, Boston VA Healthcare System, West Roxbury, Massachusetts, USA.|Division of Genetics, Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Natasha Y
NY
Frank
Division of Genetics, Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Transplant Research Program, Boston Children's Hospital, Boston, Massachusetts, USA.|Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.|School of Medical Sciences, Edith Cowan University, Joondalup, WA, Australia.
Markus H
MH
Frank
Department of Biochemistry, School of Medicine, Justus-Liebig-University of Giessen, Giessen, Germany.
Klaus T
KT
Preissner
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany. karin.scharffetter-kochanek@uniklinik-ulm.de.
Karin
K
Scharffetter-Kochanek
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D016923:Cell Death; D065206:Extracellular Traps / Q000378:metabolism; D006470:Hemorrhage / Q000473:pathology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism*; D009928:Organ Specificity; D018384:Oxidative Stress; D010447:Peptide Hydrolases / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D013482:Superoxide Dismutase; D014657:Vasculitis / Q000473:pathology
D000936:Antigen-Antibody Complex; D009195:Peroxidase; D013482:Superoxide Dismutase; D010447:Peptide Hydrolases
Mesenchymal stem cells; Neutrophil extracellular traps; Neutrophils; Superoxide dismutase; Vasculitis