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Reactive bone marrow stromal cells attenuate systemic inflammation via sTNFR1.

ABSTRACT: Excessive systemic inflammation following trauma, sepsis, or burn could lead to distant organ damage. The transplantation of bone marrow stromal cells or mesenchymal stem cells (MSCs) has been reported to be an effective treatment for several immune disorders by modulating the inflammatory response to injury. We hypothesized that MSCs can dynamically secrete systemic factors that can neutralize the activity of inflammatory cytokines. In this study, we showed that cocultured MSCs are able to decrease nuclear factor ?-B (NF?B) activation in target epithelial cells incubated in inflammatory serum conditions. Proteomic screening revealed a responsive secretion of soluble tumor necrosis factor (TNF) receptor 1 (sTNFR1) when MSCs were exposed to lipopolysaccharide (LPS)-stimulated rat serum. The responsive effect was eliminated when NF?B activation was blocked in MSCs. Intramuscular transplantation of MSCs in LPS-endotoxic rats decreased a panel of inflammatory cytokines and inflammatory infiltration of macrophages and neutrophils in lung, kidney, and liver when compared to controls. These results suggest that improvements of inflammatory responses in animal models after local transplantation of MSCs are at least, in part, explained by the NF?B-dependent secretion of sTNFR1 by MSCs.

SUBMITTER: Yagi H

PROVIDER: S-EPMC2951565 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Reactive bone marrow stromal cells attenuate systemic inflammation via sTNFR1.

Yagi Hiroshi H Soto-Gutierrez Alejandro A Navarro-Alvarez Nalu N Nahmias Yaakov Y Goldwasser Yoni Y Kitagawa Yuko Y Tilles Arno W AW Tompkins Ronald G RG Parekkadan Biju B Yarmush Martin L ML

Molecular therapy : the journal of the American Society of Gene Therapy 20100727 10

Excessive systemic inflammation following trauma, sepsis, or burn could lead to distant organ damage. The transplantation of bone marrow stromal cells or mesenchymal stem cells (MSCs) has been reported to be an effective treatment for several immune disorders by modulating the inflammatory response to injury. We hypothesized that MSCs can dynamically secrete systemic factors that can neutralize the activity of inflammatory cytokines. In this study, we showed that cocultured MSCs are able to decr ...[more]

PMID: 20664529

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Project description:BackgroundPulmonary fibrosis induced by silica dust is an irreversible, chronic, and fibroproliferative lung disease with no effective treatment at present. Previous studies have shown that early intervention with bone marrow mesenchymal stem/stromal cells (BMSCs) has positive effect on anti-pulmonary fibrosis caused by silica dust. However, early intervention using BMSCs is not practical, and the therapeutic effects of BMSCs advanced intervention on pulmonary fibrosis have rarely been reported. In this study, we investigated the effects of advanced transplantation (on the 28th day after exposure to silica suspension) of BMSCs on an established rat model of pulmonary fibrosis.MethodsSprague Dawley (SD) rats were randomly divided into four groups including (1) control group (n?=?6) which were normally fed, (2) silica model group (n?=?6) which were exposed to silica suspension (1 mL of 50 mg/mL/rat), (3) BMSC transplantation group (n?=?6) which received 1 mL BMSC suspension (2?×?106 cells/mL) by tail vein injection on the 28th day after exposure to silica suspension, and (4) BMSC-CM (conditioned medium) transplantation group (n?=?6) which received CM from the same cell number by tail vein injection on the 28th day after exposure to silica suspension. On the 56th day after exposure to silica suspension, we used computed tomography (CT), hematoxylin and eosin (H&E), and Masson's trichrome staining to evaluate the changes in lung tissue. We examined the expression of epithelial-mesenchymal transition (EMT) and Wnt/?-catenin pathway-related proteins in lung tissue using immunohistochemistry and western blotting.ResultsSuccessful construction of a pulmonary fibrosis model was confirmed by H&E and Masson's trichrome staining on the 28th day after exposure to silica suspension. On the 56th day after exposure, pulmonary CT examination showed a relieving effect of BMSCs on silica-induced pulmonary fibrosis which was confirmed by H&E and Masson's trichrome staining. Treatment of BMSCs increased the expression of epithelial marker proteins including E-cadherin (E-cad) and cytokeratin19 (CK19) and reduced the expression of fibrosis marker proteins including Vimentin (Vim) and ?-Smooth actin (?-SMA) after exposure to silica suspension. Furthermore, we found that Wnt/?-catenin signaling pathway is abnormally activated in silica-induced pulmonary fibrosis, and exogenous transplantation of BMSCs may attenuate their expression.ConclusionsBMSC transplantation inhibits the EMT to alleviate silica-induced pulmonary fibrosis in rats and the anti-fibrotic effect potentially by attenuating Wnt/?-catenin signaling. ?: ?.

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Reactive bone marrow stromal cells attenuate systemic inflammation via sTNFR1.

Publications

Reactive bone marrow stromal cells attenuate systemic inflammation via sTNFR1.

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