Gene expression profile reveals that STAT2 is involved in the immunosuppressive function of human bone marrow-derived mesenchymal stem cells

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.