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. 2023 Aug 15:385:12-20.
doi: 10.1016/j.toxlet.2023.08.006. Epub 2023 Aug 10.

Cigarette smoke attenuates mesenchymal stem cell-based suppression of immune cell-driven acute liver failure

Dragica Pavlovic  1 , Dragana Miloradovic  1 , Milica Dimitrijevic Stojanovic  2 , Carl Randall Harrell  3 , Riccardo Polosa  4 , Sonja Rust  5 , Giovanni Li Volti  6 , Massimo Caruso  6 , Vladimir Jakovljevic  7 , Valentin Djonov  8 , Vladislav Volarevic  9
Affiliations
Free article

Cigarette smoke attenuates mesenchymal stem cell-based suppression of immune cell-driven acute liver failure

Dragica Pavlovic et al. Toxicol Lett. .
Free article

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 (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.

Keywords: Acute hepatitis; Cigarette smoke; Hepatoprotection; Immunosuppression; Mesenchymal stem cells; Therapy.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.