Human gingival tissue-derived mesenchymal stem cells inhibit proliferation and invasion of rheumatoid fibroblast-like synoviocytes via the CD39/CD73 signaling pathway

BackgroundGingiva-derived mesenchymal stem cells (GMSCs) suppress immune and inflammatory responses in experimental arthritis models. Here, we determined whether GMSCs suppress the proliferation and invasion of rheumatoid arthritis fibroblast-like synoviocytes (RA FLSs). MethodsSurface markers of GMSCs were analyzed by flow cytometry. mRNA expression of matrix metalloproteinases and pro-inflammatory cytokine in RA FLSs was measured by quantitative polymerase chain reaction (PCR). RA FLS proliferation was analyzed by a 5-ethynyl-2 & PRIME;-deoxyuridine assay. To explore the molecular mechanisms, we assessed the effect of GMSCs on RA FLS proliferation by adding indoleamine-2,3-dioxygenase (IDO), CD39, or CD73 inhibitors. The invasion was analyzed by a transwell assay. The anti-inflammatory effects of GMSCs were assessed in a type II collagen-induced arthritis (CIA) mouse model. ResultsCompared with human dermal fibroblast, GMSCs displayed a higher expression of CD39. Interleukin (IL)-8, IL-6, MMP-1, MMP-3, MMP-13, and monocyte chemoattractant protein-1 mRNA were all decreased in RA FLSs after incubation with GMSCs. GMSCs significantly reduced RA FLS proliferation in a dose-dependent manner in vitro, which was partly dependent on CD39/CD73 signaling. GMSCs significantly impeded the invasive capacity of RA FLSs in a dose-dependent manner in vitro. GMSCs infusion delayed arthritis onset and reduced arthritis scores in the CIA model. ConclusionGMSCs are effective to inhibit the aggressive behavior of RA FLSs and treat experimental arthritis, implying their therapeutic potential in RA patients.