Suppression of Neutrophil‐Mediated Tissue Damage—A Novel Skill of Mesenchymal Stem Cells. (27th June 2016)

• Record Type: Journal Article
• Authors: Jiang, Dongsheng; Muschhammer, Jana; Qi, Yu; Kügler, Andrea; de Vries, Juliane C.; Saffarzadeh, Mona; Sindrilaru, Anca; Beken, Seppe Vander; Wlaschek, Meinhard; Kluth, Mark A.; Ganss, Christoph; Frank, Natasha Y.; Frank, Markus H.; Preissner, Klaus T.; Scharffetter‐Kochanek, Karin
• Is Part Of: Stem cells. Volume 34:Number 9(2016:Sep.)
• Page Start: 2393
• Page End: 2406
• Publication Date: 2016-06-27
• Subjects: Mesenchymal stem cells -- Neutrophils -- Neutrophil extracellular traps -- Vasculitis -- Superoxide dismutase; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2417
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract : 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 Abstract : Scheme of adaptive mesenchymal stem cell (MSC) responses to unrestrained neutrophil activation. Immune complexes inside and outside the vessel lead to unrestrained neutrophil activation with enhanced generation and release of O 2 − . which can stimulate neutrophil extracellular trap formation with expulsion of chromatin decorated with granules and highly concentrated myeloperoxidase, neutrophil elastase, and matrix metalloproteinase‐9, neutrophil death with spillage of their toxic cargo leading to tissue damage and tissue break down. Further damage to macromolecules occur by O 2 − . and derivatives thereof like hydrogen peroxide (H2 O2 ), peroxynitrate (ONNO . ) and hydroxyl radicals (HO . ). MSCs are able to mount an adaptive response to unrestrained neutrophil activation, with the release of O 2 − . detoxifying extracellular superoxide dismutase and intercellular adhesion molecule 1/CD18 dependent engulfment of dying neutrophils thus preventing the spillage of their toxic cargo. By employing independent strategies MSCs effectively protect from tissue damage due to unrestrained neutrophil activation.