Abstract
IntroductionMultipotent stromal cells (MSCs) are currently in clinical trials for a number of inflammatory diseases. Recent studies have demonstrated the ability of MSCs to attenuate inflammation in rodent models of acute lung injury (ALI) suggesting that MSCs may also be beneficial in treating ALI.MethodsTo better understand how human MSCs (hMSCs) may act in ALI, the lungs of immunocompetent mice were exposed to lipopolysaccharide (LPS) and four hours later bone marrow derived hMSCs were delivered by oropharyngeal aspiration (OA). The effect of hMSCs on lung injury was assessed by measuring the lung wet/dry weight ratio and total protein in bronchoalveolar lavage (BAL) fluid 24 or 48 h after LPS. BAL fluid was also analyzed for the presence of inflammatory cells and cytokine expression by multiplex immunoassay. Microarray analysis of total RNA isolated from treated and untreated lungs was performed to elucidate the mechanism(s) involved in hMSC modulation of lung inflammation.ResultsAdministration of hMSCs significantly reduced the expression of pro-inflammatory cytokines, neutrophil counts and total protein in bronchoalveolar lavage. There was a concomitant reduction in pulmonary edema. The anti-inflammatory effects of hMSCs were not dependent on localization to the lung, as intraperitoneal administration of hMSCs also attenuated LPS-induced inflammation in the lung. Microarray analysis revealed significant induction of tumor necrosis factor (TNF)-α-induced protein 6 (TNFAIP6/TSG-6) expression by hMSCs 12 h after OA delivery to LPS-exposed lungs. Knockdown of TSG-6 expression in hMSCs by RNA interference abrogated most of their anti-inflammatory effects. In addition, intra-pulmonary delivery of recombinant human TSG-6 reduced LPS-induced inflammation in the lung.ConclusionsThese results show that hMSCs recapitulate the observed beneficial effects of rodent MSCs in animal models of ALI and suggest that the anti-inflammatory properties of hMSCs in the lung are explained, at least in part, by activation of hMSCs to secrete TSG-6.
Highlights
Multipotent stromal cells (MSCs) are currently in clinical trials for a number of inflammatory diseases
To elucidate the role of human MSCs (hMSCs) in acute lung injury (ALI), the lungs of immunocompetent mice were exposed to LPS and 4 h later 5 × 105 hMSCs, or human lung fibroblasts (HLFs) as control, were delivered by oropharyngeal aspiration (OA)
Lungs from mice exposed to LPS had a lung injury index of 5.6, whereas lungs from mice treated with hMSCs after LPS-exposure had a significantly lower lung injury index of 3.6 (P < 0.05) (Figure 1b)
Summary
Multipotent stromal cells (MSCs) are currently in clinical trials for a number of inflammatory diseases. ALI is a syndrome of widespread lung inflammation and increased pulmonary vascular permeability resulting in MSCs are fibroblast-like cells characterized by their ability to self-renew and undergo differentiation into mesenchymal lineage cell types including bone, cartilage, adipose tissue, muscle and tendon [4]. MSCs have been isolated from the bone marrow and the connective tissue of almost all organs including adipose, periosteum, synovial fluid, muscle, hair follicles, root of deciduous teeth, articular cartilage, placenta, dermis, umbilical cord, Wharton’s jelly, lung, liver and spleen [4,5,6]. MSCs are currently in clinical trials for treatment of a number of human diseases including osteogenesis imperfecta, osteoarthritis, graft-versus-host disease, multiple sclerosis, types 1 and 2 diabetes, Crohn’s disease, acute kidney injury, acute myocardial infarction, ischemic heart failure, and chronic obstructive pulmonary disease [8]
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