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Mesenchymal stem cells ameliorate Th1-induced pre-eclampsia-like symptoms in mice via the suppression of TNF-α expression.

Liu L, Zhao G, Fan H, Zhao X, Li P, Wang Z, Hu Y, Hou Y - PLoS ONE (2014)

Bottom Line: The MSCs not only exhibited differentiation and self-renewal capacities, they also possessed immunomodulatory functions and secreted some soluble mediators including IL-6, TGF-β, IDO, VEGF and COX-2.Most importantly, the MSCs were specifically provided with the ability to suppress T cells proliferation by IDO in response to inflammatory cytokine IFN-γ.Strikingly, MSCs-based therapy significantly ameliorated both clinical and histopathological severity of PE symptoms including decreasing the blood pressure and proteinuria, suppressing glomerulonephritis, protecting the feto-placental development.

View Article: PubMed Central - PubMed

Affiliation: Immunology Lab, Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.

ABSTRACT
Pre-eclampsia (PE) is thought to be a pregnancy-induced autoimmune disease. Despite several strategies carried out for targeting specific factors relevant to its pathogenesis, PE remains potentially fatal to some patients. Here, we reported a way to isolate mesenchymal stem cells (MSCs) from decidua. The MSCs not only exhibited differentiation and self-renewal capacities, they also possessed immunomodulatory functions and secreted some soluble mediators including IL-6, TGF-β, IDO, VEGF and COX-2. Most importantly, the MSCs were specifically provided with the ability to suppress T cells proliferation by IDO in response to inflammatory cytokine IFN-γ. Moreover, we developed a Th1 cell-induced PE mouse model which displayed a high level of pathogenesis factor TNF-α. Strikingly, MSCs-based therapy significantly ameliorated both clinical and histopathological severity of PE symptoms including decreasing the blood pressure and proteinuria, suppressing glomerulonephritis, protecting the feto-placental development. The therapy also reversed abnormal TNF-α expression in uterine and splenic lymphocytes. These data suggest that MSCs may ameliorate Th1-induced PE-like symptoms in mice via the suppression of TNF-α and MSCs-based therapy may provide a potential novel method for PE.

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MSCs -based therapy reverse the cytokine abnormal in PE uterine and splenic lymphocytes.(A): QPCR analysis of the expression of TNF-α, IFN-γ and IL-4 in uterine tissue. Relative to GAPDH. (B): An illustration of the percentage of uterine lymphocytes positive for TNF-α, IFN-γ and IL-4 in pregnant mice that received PBS (n = 5) or activated Th1-like cells(n = 5) or activated Th1-like cells and MSCs(n = 5), as analyzed by flow cytometry. (C): Spleen lymphocytes were analyzed for the expression of activation molecules using anti-CD69 or anti-CCR5 monoclonal antibodies or analyzed for the expression of intracellular IFN-γ, IL-4 and TNF-α. Spleen lymphocytes were treated with PMA for the last 4 hours of cultures before the analysis. All data are representative of three independent experiments. *, p<0.05, **, p<0.01 and ***, p<0.001.
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pone-0088036-g005: MSCs -based therapy reverse the cytokine abnormal in PE uterine and splenic lymphocytes.(A): QPCR analysis of the expression of TNF-α, IFN-γ and IL-4 in uterine tissue. Relative to GAPDH. (B): An illustration of the percentage of uterine lymphocytes positive for TNF-α, IFN-γ and IL-4 in pregnant mice that received PBS (n = 5) or activated Th1-like cells(n = 5) or activated Th1-like cells and MSCs(n = 5), as analyzed by flow cytometry. (C): Spleen lymphocytes were analyzed for the expression of activation molecules using anti-CD69 or anti-CCR5 monoclonal antibodies or analyzed for the expression of intracellular IFN-γ, IL-4 and TNF-α. Spleen lymphocytes were treated with PMA for the last 4 hours of cultures before the analysis. All data are representative of three independent experiments. *, p<0.05, **, p<0.01 and ***, p<0.001.

Mentions: Compared with normal pregnancy mouse, Th1-induced PE mice showed aberrant expression levels of TNF-α in uterine and TNF-α and IL-4 in splenic lymphocytes, but no obvious difference in the expression of the IFN-γ and IL-4 in uterine orCCR5, CD69 and IFN-γ in splenic lymphocytes [Fig. 5A, B, C]. Importantly, MSCs significantly attenuated TNF-α expression in uterine and splenic lymphocytes [Fig. 5B–C]. These findings suggest that MSCs may ameliorate Th1-induced PE-like mice mainly via the suppression of TNF-α.


Mesenchymal stem cells ameliorate Th1-induced pre-eclampsia-like symptoms in mice via the suppression of TNF-α expression.

Liu L, Zhao G, Fan H, Zhao X, Li P, Wang Z, Hu Y, Hou Y - PLoS ONE (2014)

MSCs -based therapy reverse the cytokine abnormal in PE uterine and splenic lymphocytes.(A): QPCR analysis of the expression of TNF-α, IFN-γ and IL-4 in uterine tissue. Relative to GAPDH. (B): An illustration of the percentage of uterine lymphocytes positive for TNF-α, IFN-γ and IL-4 in pregnant mice that received PBS (n = 5) or activated Th1-like cells(n = 5) or activated Th1-like cells and MSCs(n = 5), as analyzed by flow cytometry. (C): Spleen lymphocytes were analyzed for the expression of activation molecules using anti-CD69 or anti-CCR5 monoclonal antibodies or analyzed for the expression of intracellular IFN-γ, IL-4 and TNF-α. Spleen lymphocytes were treated with PMA for the last 4 hours of cultures before the analysis. All data are representative of three independent experiments. *, p<0.05, **, p<0.01 and ***, p<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928118&req=5

pone-0088036-g005: MSCs -based therapy reverse the cytokine abnormal in PE uterine and splenic lymphocytes.(A): QPCR analysis of the expression of TNF-α, IFN-γ and IL-4 in uterine tissue. Relative to GAPDH. (B): An illustration of the percentage of uterine lymphocytes positive for TNF-α, IFN-γ and IL-4 in pregnant mice that received PBS (n = 5) or activated Th1-like cells(n = 5) or activated Th1-like cells and MSCs(n = 5), as analyzed by flow cytometry. (C): Spleen lymphocytes were analyzed for the expression of activation molecules using anti-CD69 or anti-CCR5 monoclonal antibodies or analyzed for the expression of intracellular IFN-γ, IL-4 and TNF-α. Spleen lymphocytes were treated with PMA for the last 4 hours of cultures before the analysis. All data are representative of three independent experiments. *, p<0.05, **, p<0.01 and ***, p<0.001.
Mentions: Compared with normal pregnancy mouse, Th1-induced PE mice showed aberrant expression levels of TNF-α in uterine and TNF-α and IL-4 in splenic lymphocytes, but no obvious difference in the expression of the IFN-γ and IL-4 in uterine orCCR5, CD69 and IFN-γ in splenic lymphocytes [Fig. 5A, B, C]. Importantly, MSCs significantly attenuated TNF-α expression in uterine and splenic lymphocytes [Fig. 5B–C]. These findings suggest that MSCs may ameliorate Th1-induced PE-like mice mainly via the suppression of TNF-α.

Bottom Line: The MSCs not only exhibited differentiation and self-renewal capacities, they also possessed immunomodulatory functions and secreted some soluble mediators including IL-6, TGF-β, IDO, VEGF and COX-2.Most importantly, the MSCs were specifically provided with the ability to suppress T cells proliferation by IDO in response to inflammatory cytokine IFN-γ.Strikingly, MSCs-based therapy significantly ameliorated both clinical and histopathological severity of PE symptoms including decreasing the blood pressure and proteinuria, suppressing glomerulonephritis, protecting the feto-placental development.

View Article: PubMed Central - PubMed

Affiliation: Immunology Lab, Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.

ABSTRACT
Pre-eclampsia (PE) is thought to be a pregnancy-induced autoimmune disease. Despite several strategies carried out for targeting specific factors relevant to its pathogenesis, PE remains potentially fatal to some patients. Here, we reported a way to isolate mesenchymal stem cells (MSCs) from decidua. The MSCs not only exhibited differentiation and self-renewal capacities, they also possessed immunomodulatory functions and secreted some soluble mediators including IL-6, TGF-β, IDO, VEGF and COX-2. Most importantly, the MSCs were specifically provided with the ability to suppress T cells proliferation by IDO in response to inflammatory cytokine IFN-γ. Moreover, we developed a Th1 cell-induced PE mouse model which displayed a high level of pathogenesis factor TNF-α. Strikingly, MSCs-based therapy significantly ameliorated both clinical and histopathological severity of PE symptoms including decreasing the blood pressure and proteinuria, suppressing glomerulonephritis, protecting the feto-placental development. The therapy also reversed abnormal TNF-α expression in uterine and splenic lymphocytes. These data suggest that MSCs may ameliorate Th1-induced PE-like symptoms in mice via the suppression of TNF-α and MSCs-based therapy may provide a potential novel method for PE.

Show MeSH
Related in: MedlinePlus