Pavlovic, DragicaDragicaPavlovicMiloradovic, DraganaDraganaMiloradovicStojanovic, Milica DimitrijevicMilica DimitrijevicStojanovicHarrell, Carl RandallCarl RandallHarrellPolosa, RiccardoRiccardoPolosaRust, SonjaSonjaRustVolti, Giovanni LiGiovanni LiVoltiCaruso, MassimoMassimoCarusoJakovljevic, VladimirVladimirJakovljevicDjonov, Valentin GeorgievValentin GeorgievDjonov0000-0002-5062-1169Volarevic, VladislavVladislavVolarevic2024-10-252024-10-252023-08-15https://boris-portal.unibe.ch/handle/20.500.12422/169251Detrimental 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 (MSCWS-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 (MSCCM). In contrast to MSCCM, which efficiently attenuated α-GalCer-induced hepatitis, MSCWS-CM were not able to prevent hepatocyte injury and liver inflammation. MSCWS-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+MSCCM-treated mice compared to α-GalCer+saline-treated animals, this phenomenon was not observed in α-GalCer-injured mice that received MSCWS-CM. MSCWS-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 MSCCM. Similarly as it was observed in mice, MSCWS-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.enacute hepatitis cigarette smoke hepatoprotection immunosuppression mesenchymal stem cells therapy600 - Technology::610 - Medicine & healtharticle10.48350/1854293757297010.1016/j.toxlet.2023.08.006