Human multipotent stromal cells attenuate lipopolysaccharide-induced acute lung injury in mice via secretion of tumor necrosis factor-α-induced protein 6

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.

Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis

“…In a murine model of lung injury using LPS, MSCs upregulated expression of TSG-6, while decreasing cytokine levels and infl ammatory cell counts in BAL fl uid. 34 Knockdown of TSG-6 expression in MSCs nullifi ed most of these anti-infl ammatory eff ects when MSCs were given after injury. In support of these fi ndings, other studies show that intravenous administration of TSG-6 reduced alveolar concentrations of pro infl ammatory cytokines and improved survival in a bleomycin lung injury model.…”

Alveolar Macrophages Are Critical for the Inhibition of Allergic Asthma by Mesenchymal Stromal Cells

“…Inhibition of allergic asthma by hMSC administration is dependent on AM-mediated induction of IL-10 production from other cell sources TSG-6 is an anti-inflammatory protein found to be secreted by hMSCs activated in the lungs (7); it interacts with macrophages to decrease release of proinflammatory mediators (27). In a mouse model of acute lung injury, knockdown of TSG-6 expression in hMSCs by RNA interference abrogated the anti-inflammatory effects of hMSCs, whereas local administration of recombinant TSG-6 reduced inflammation in the lungs (28). We therefore measured AHR in OVA-sensitized mice administered TSG-6 via the intranasal route instead of i.v.…”

Human cytomegalovirus infection of human adipose-derived stromal/stem cells restricts differentiation along the adipogenic lineage

“…Data suggests that the therapeutic effects of ASCs are mediated in large part by release of paracrine factors that modulate inflammatory and immune responses or that enhance tissue repair. [5][6][7][8] Additionally, ASCs can differentiate into various tissues including fat, bone and cartilage 9 and thus have potential for regenerative stem cell therapies. 10,11 Despite promising therapeutic potential of ASCs, little is known about their susceptibility to infectious agents.…”