Abstract
Currently available therapies for rheumatoid arthritis (RA) are inadequate to alleviate the inflammation and reduce joint damage. While the immune-regulatory effect of human mesenchymal/stromal stem cells (MSCs) extracellular vesicles (EVs) has been tested in many inflammation-related diseases, little is known regarding their effect on patients with RA. Thus, we assessed the effect of human MSCs and MSC-EVs (from naïve or IFN-β-primed MSCs) on CD4+ T cells from patients with RA. Moreover, we investigated the effect of MSC-EVs on RA patients-derived synovial fibroblasts (FLS). MSC-EVs were prepared using a PEG precipitation followed by ultracentrifugation-based protocol. Applied to RA CD4+ T cells, EVs from IFN-β-primed MSCs, suppressed the expression of more key RA-associated cytokines (IL-4, GM-CSF IFN-γ, IL-2, TNF-α), and decreased CD4+ T-cell polyfunctionality than MSCs or EVs from naïve MSCs. MSCs mediated a slight decrease in the frequency of T-regulatory cells, while MSC-EVs rescued the frequency of T-regulatory cells. MSCs significantly inhibited CD4+ T-cell proliferation (P < .05), while no inhibition was observed in response to EV preparations. EVs from IFN-β-primed MSCs inhibited (P < .01) RA FLS migration and downregulated (P < .05) RA FLS surface markers CD34 and HLA-DR. Collectively, we demonstrated the immune-modulatory function of MSCs and their derived EVs in RA CD4+ T cells, which could be further enhanced by priming MSCs with IFN-β. Moreover, EVs from IFN-β-primed MSCs more efficiently inhibit RA FLS migration, and expression of RA FLS-related surface markers, suggesting these EVs as a potent therapy for RA.