Epigenetic modification of mesenchymal stromal cells enhances their suppressive effects on the Th17 responses of cells from rheumatoid arthritis patients

Abstract

BackgroundThe aim of this study was to investigate if epigenetically modified human mesenchymal stromal cells (hMSCs) can regulate the Th17-related immune responses.MethodsWe tested epigenetic drug combinations at various doses and selected the four combinations that resulted in maximal interleukin (IL)-10 and indoleamine 2,3-dioxygenase gene expression in hMSCs. We examined the effects of epigenetically modified hMSCs (epi-hMSCs) on CD4+ T-cell proliferation and inflammatory cytokine secretion under Th0- and Th17-polarizing conditions using mixed lymphocyte reactions and enzyme-linked immunosorbent assays (ELISAs). We determined Th17 cytokine levels and the percentage of Th17 cells among synovial fluid mononuclear cells (SFMCs) from rheumatoid arthritis (RA) patients by ELISA and flow cytometry.ResultsEpi-hMSCs inhibited the development of IL-17-producing cells in culture. The percentages of IL-17+ and interferon (IFN)-γ+ cells among peripheral blood mononuclear cells from healthy donors were lower under both the Th0 and Th17 conditions in the presence of epi-hMSCs than in the presence of no or untreated hMSCs. Epi-hMSC-treated RA patient SFMCs secreted lower levels of IL-17 and IFN-γ than RA patient SFMCs cultured without hMSCs or with untreated hMSCs.ConclusionsAn optimal combination of hypomethylating agents and histone deacetylase inhibitors can enhance the immunomodulatory potential of hMSCs, which may be useful for RA treatment.

Epigenetic Regulation in the Pathogenesis of Sjögren Syndrome and Rheumatoid Arthritis

“…Therefore, research that specifically focuses on elucidating the epigenetic control in specific subpopulations of immune cells will provide new insights into the pathogenesis of autoimmune diseases and will open up new ways to develop novel therapeutic approaches that target epigenetic mechanisms, such as DNA methylation, histone PTMs, and regulating miRNAs expression. HDAC inhibitors (HDACi) are proposed as a therapeutic strategy for RA (Hsieh et al, 2014; Cantley et al, 2015; Oh et al, 2017; Angiolilli et al, 2018; Kim et al, 2018;). HDACi is a good therapeutic approaches because it helps to lower inflammation levels through vascular cell adhesion molecule-1 (VCAM), intercellular adhesion molecule-1 (ICAM), and E-selectin (ESEL) levels, which could contribute to immunosuppression (Inoue et al, 2006).…”

Immunomodulatory Effects of Mesenchymal Stem Cells and Mesenchymal Stem Cell-Derived Extracellular Vesicles in Rheumatoid Arthritis

“…In addition, different conditions also influence the effect of MSCs. For example, epigenetically-modified MSCs (combination of hypomethylating agents and histone deacetylase inhibitors) have a high immunoregulatory effect in RA ( 68 ). Consequently, determining how long the immunomodulatory effects of MSCs last will need to be solved in clinical practice, the results of which could provide a theoretical basis and support for their use in the treatment of RA.…”

Control of mesenchymal stem cell biology by histone modifications

“…Efforts have been made to promote the therapeutic effects of MSCs through genetic modification and pretreatment (priming) before MSC administration [161][162][163][164]. For example, treatment with combinations of DNA-hypomethylating agents and HDAC inhibitors has recently been shown to enhance the anti-inflammatory effects of MSCs [165]. Such epigenetically modified MSCs express increased levels of IL-10 and IDO and inhibit T cell differentiation of peripheral blood mononuclear cells (PBMCs) under T0 and T17 conditions.…”