title: Gene expression profile reveals that STAT2 is involved in the immunosuppressive function of human bone marrow-derived mesenchymal stem cells.
abstract: Emerging evidence of the potent immunosuppressive activity of mesenchymal stem cells (MSCs) by modulation of both innate and adaptive immune responses enables MSCs to be developed as a promising therapeutic modality for immune-related or inflammatory diseases. However, it is not clearly understood how MSCs exert their immunosuppressive effects on immune cells under inflammatory conditions. Using human bone marrow (BM)-derived clonal MSCs (hcMSCs), we obtained and analyzed a differentially expressed gene profile when stimulated with the inflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) to find novel candidate factors responsible for MSC immunomodulation. Microarray analysis showed that 5650 genes were upregulated and 5862 genes were downregulated with the cutoff of 2-fold expression change. Among these, the ICOSLG and STAT2 genes were drastically upregulated 173-fold and 154-fold, respectively. Reverse transcription-polymerase chain reaction analysis confirmed the microarray data. To evaluate whether their increased expression is related to MSC-mediated immunosuppression,siRNA-induced ICOSLG- or STAT2-knockdown hcMSCs were assessed for their T cell suppressive activity. We demonstrated that STAT2 but not ICOSLG is functionally involved in the immunosuppressive activity of hcMSCs as a novel regulator under inflammatory conditions. Gene ontology and pathway analyses further support the immunomodulatory function of hcMSCs when inflammatory stimulation was provided.Taken together, this study provides an informative genome-wide gene expression profile and molecular evidence for understanding the mechanisms underlying the modulation of immune cells by human BM-derived MSCs under inflammatory conditions.
authors.affiliation: Inha University Hospital, Incheon, Republic of Korea.
authors.forename: TacGhee
authors.initials: T
authors.lastname: Yi
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Lee
authors.forename: Myung-Shin
authors.initials: MS
authors.lastname: Jeon
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kwon
authors.forename: Sun U
authors.initials: SU
authors.lastname: Song
mesh_terms: D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling / Q000379:methods; D055785:Gene Knockdown Techniques / Q000379:methods; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D007155:Immunologic Factors / Q000235:genetics / Q000276:immunology; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D050795:STAT2 Transcription Factor / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: C498514:ICOSLG protein, human; D007155:Immunologic Factors; D060945:Inducible T-Cell Co-Stimulator Ligand; D034741:RNA, Small Interfering; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma