ABSTRACT
Increasing studies have demonstrated that interferon gamma (IFN-γ),which serves as a critical inflammatory cytokine,is essential to induce the immunosuppressive effects of mesenchymal stem cells (MSCs).However,the mechanisms underlying the enhanced immunosuppressive effects of IFN-γ-stimulated MSCs (γMSCs) are not fully understood.MSC-derived rnicrovesicles (MSC-MVs) have been viewed as potential pivotal mediators of the immunosuppressive effects of MSCs.Moreover,microRNAs (miRNAs) are important regulators of immunological processes and can be shuttled from cell to cell by MVs.The aim of our study was to analyze the the miRNA expression signature of MVs derived from γMSCs (γMSC-MVs),which may provide better understanding of the immunosuppressive property of their parent cells.Through miRNA microarray and bioinformatics analysis,we found 62 significantly differentially expressed miRNAs (DEMs) in γMSC-MVs compared with MSC-MVs.And the potential target genes and signaling pathways regulated by DEMs were predicted and analyzed.Interestingly,many DEMs and predicted signaling pathways had been.demonstrated to be involved in immunoregulation.Furthermore,the network between immunoregulation-related pathways and relevant DEMs was constructed.Collectively,our research on the miRNA repertoires of γMSC-MVs not only provides new perspectives into the mechanisms underlying the enhanced immunosuppressive property of γMSCs,but also paves the way to clinical application of these potent organelles in the future.
ABSTRACT
P-450-dependent epoxygenase pathway of arachidonic acid and the products of epoxyeicosatrienoic acids (EETs) have been demonstrated to be involved in angiogenesis and tumor progression.This study examined the expression of EETs and the role of the pathway in the angiogenesis of multiple myeloma (MM).MM cell lines of U266 and RPMI8226 were cultured,and the EETs levels (11,12-EET and 14,15-EET) in the supematant were determined by ELISA.Human umbilical vein endothelial cells (HUVECs) were cultured and used for analysis of the angiogenesis activity of the two MM cell lines,which was examined both in vitro and in vivo by employing MTT,chemotaxis,tube formation and matrigel plug assays.11,12-EET and 14,15-EET were found in the supematant of the cultured MM cells.The levels of the two EETs in the supernatant of U266 cells were significantly higher than those in the RPMI8226 cell supematant (P＜0.05),and the levels paralleled the respective angiogenesis activity of the two different MM cell lines.17-octadecynoic acid (17-ODYA),as a specific inhibitor of P450 enzyme,suppressed HUVECs proliferation and tube formation induced by MM cells.Furthermore,17-ODYA decreased the EET levels in the supernatant of MM cells.These results suggest that EETs may play an important role in the angiogenesis of MM,and the inhibitor 17-ODYA suppresses this effect.