title: Licensing by Inflammatory Cytokines Abolishes Heterogeneity of Immunosuppressive Function of Mesenchymal Stem Cell Population.
abstract: When mesenchymal stem cells (MSCs) are used for therapy of immunological pathologies, they get into an inflammatory environment, altering the effectiveness of the treatment. To establish the impact of environmental inflammatory factors on MSCs' immunofunction in the mirror of intrinsic heterogeneity of mouse MSC population, individual MSC clones were generated and characterized. Adipogenic but not osteogenic differentiation and pro-angiogenic activity of five independent MSC cell lines were similar. Regarding osteogenic differentiation, clones MSC3 and MSC6 exhibited poorer capacity than MSC2, MSC4, and MSC5. To study the immunosuppressive heterogeneity, in vitro and in vivo experiments have been carried out using T-cell proliferation assay and delayed-type hypersensitivity (DTH) response, respectively. A remarkable difference was found between the clones in their ability to inhibit T-cell proliferation in the following order: MSC2≥MSC5>MSC4>MSC3 >> MSC6. Nevertheless, the differences between the immunosuppressive activities of the individual clones disappeared on pretreatment of the cells with pro-inflammatory cytokines, a procedure called licensing. Stimulation of all clones with IFN-γ and TNF-α resulted in elevation of their inhibitory capability to a similar level. Nitric oxide (NO) and prostaglandin E2 (PGE2) were identified as major mediators of immunofunction of the MSC clones. The earlier findings were also supported by in vivo results. Without licensing, MSC2 inhibited DTH response, while MSC6 did not affect DTH response. In contrast, prestimulation of MSC6 with inflammatory cytokines resulted in strong suppression by this clone as well. Here, we have showed that MSC population is functionally heterogeneous in terms of immunosuppressive function; however, this variability is largely reduced under pro-inflammatory conditions.
authors.affiliation: 1 Institute of Genetics, Biological Research Centre , Hungarian Academy of Sciences, Szeged, Hungary .
authors.forename: Enikő
authors.initials: E
authors.lastname: Szabó
authors.affiliation: 1 Institute of Genetics, Biological Research Centre , Hungarian Academy of Sciences, Szeged, Hungary .
authors.forename: Roberta
authors.initials: R
authors.lastname: Fajka-Boja
authors.affiliation: 1 Institute of Genetics, Biological Research Centre , Hungarian Academy of Sciences, Szeged, Hungary .
authors.forename: Éva
authors.initials: É
authors.lastname: Kriston-Pál
authors.affiliation: 1 Institute of Genetics, Biological Research Centre , Hungarian Academy of Sciences, Szeged, Hungary .
authors.forename: Ákos
authors.initials: Á
authors.lastname: Hornung
authors.affiliation: 1 Institute of Genetics, Biological Research Centre , Hungarian Academy of Sciences, Szeged, Hungary .
authors.forename: Ildikó
authors.initials: I
authors.lastname: Makra
authors.affiliation: 2 Stem Cell Biology Unit, National Blood Service , Budapest, Hungary .
authors.forename: Gyöngyi
authors.initials: G
authors.lastname: Kudlik
authors.affiliation: 2 Stem Cell Biology Unit, National Blood Service , Budapest, Hungary .
authors.forename: Ferenc
authors.initials: F
authors.lastname: Uher
authors.affiliation: 1 Institute of Genetics, Biological Research Centre , Hungarian Academy of Sciences, Szeged, Hungary .
authors.forename: Róbert László
authors.initials: RL
authors.lastname: Katona
authors.affiliation: 1 Institute of Genetics, Biological Research Centre , Hungarian Academy of Sciences, Szeged, Hungary .
authors.forename: Éva
authors.initials: É
authors.lastname: Monostori
authors.affiliation: 1 Institute of Genetics, Biological Research Centre , Hungarian Academy of Sciences, Szeged, Hungary .
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Czibula
mesh_terms: D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D015232:Dinoprostone / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000276:immunology; D010012:Osteogenesis / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D015232:Dinoprostone