Cigarette smoke attenuates mesenchymal stem cell-based suppression of immune cell-driven acute liver failure
D. Pavlović, Dragana Miloradović, Milica Dimitrijevic Stojanovic, Carl Randall Harrell, Riccardo Polosa, Sonja Rust, Giovanni Li Volti, Massimo Caruso, Vladimir Jakovljević, Valentin Djonov, Vladislav Volarević
Abstract
Detrimental effects of smoking on mesenchymal stem cell (MSC)-dependent immunosuppression and hepatoprotection are unknown. Herewith, by using α-galactosylceramide (α-GalCer)-induced liver injury, a well-established murine model of fulminant hepatitis, we examined molecular mechanisms which were responsible for negative effects of cigarette smoke on MSC-dependent immunomodulation . MSC which were grown in cigarette smoke-exposed medium (MSC WS-CM ) obtained pro-inflammatory phenotype, were not able to optimally produce hepatoprotective and immunosuppressive cytokines (TGF-β, HGF , IL-10, NO , KYN), and secreted significantly higher amounts of inflammatory cytokines (IFN-γ, TNF-α, IL-17, IL-6) than MSC that were cultured in standard medium never exposed to cigarette smoke (MSC CM ). In contrast to MSC CM , which efficiently attenuated α-GalCer-induced hepatitis, MSC WS-CM were not able to prevent hepatocyte injury and liver inflammation. MSC WS-CM had reduced capacity for the suppression of liver-infiltrated inflammatory macrophages, dendritic cells (DCs) and lymphocytes. Although significantly lower number of IL-12-producing macrophages and DCs, TNF-α, IFN-γ or IL-17-producing CD4 + and CD8 +T lymphocytes, NK and NKT cells were noticed in the livers of α-GalCer+MSC CM -treated mice compared to α-GalCer+saline-treated animals, this phenomenon was not observed in α-GalCer-injured mice that received MSC WS-CM . MSC WS-CM could not induce expansion of anti-inflammatory IL-10-producing FoxP3 +CD4 + and CD8 + T regulatory cells and were not able to create immunosuppressive microenvironment in the liver as MSC CM . Similarly as it was observed in mice, MSC WS-CM were not able to optimally inhibit production of inflammatory and hepatototoxic cytokines in activated human Th1/Th17 and NKT1/NKT17 cells, confirming the hypothesis that cigarette smoke significantly attenuates therapeutic potential of MSC in cell-based immunotherapy of inflammatory liver diseases.