Chen, MaogenSu, WenruLin, XiaohongGuo, ZhiyongWang, JulieZhang, QunzhouBrand, DavidRyffel, BernhardHuang, JiefuLiu, ZhongminHe, XiaoshunLe, Anh D2023-05-222023-05-222013-05-012022-06-15https://repository.upenn.edu/handle/20.500.14332/9209Objective Current approaches offer no cures for rheumatoid arthritis (RA). Accumulating evidence has revealed that manipulation of bone marrow-derived mesenchymal stem cells (BM-MSCs) may have the potential to control or even prevent RA, but BM-MSC-based therapy faces many challenges, such as limited cell availability and reduced clinical feasibility. This study in mice with established collagen-induced arthritis (CIA) was undertaken to determine whether substitution of human gingiva-derived mesenchymal stem cells (G-MSCs) would significantly improve the therapeutic effects. Methods CIA was induced in DBA/1J mice by immunization with type II collagen and Freund's complete adjuvant. G-MSCs were injected intravenously into the mice on day 14 after immunization. In some experiments, intraperitoneal injection of PC61 (anti-CD25 antibody) was used to deplete Treg cells in arthritic mice. Results Infusion of G-MSCs in DBA/1J mice with CIA significantly reduced the severity of arthritis, decreased the histopathology scores, and down-regulated the production of inflammatory cytokines (interferon-γ and interleukin-17A). Infusion of G-MSCs also resulted in increased levels of CD4+CD39+FoxP3+ cells in arthritic mice. These increases were noted early after infusion in the spleens and lymph nodes, and later after infusion in the synovial fluid. The FoxP3+ Treg cells that were increased in frequency mainly consisted of Helios-negative cells. When Treg cells were depleted, infusion of G-MSCs partially interfered with the progression of CIA. Pretreatment of G-MSCs with a CD39 or CD73 inhibitor significantly reversed the protective effect of G-MSCs on CIA. Conclusion The role of G-MSCs in controlling the development and severity of CIA mostly depends on CD39/CD73 signals and partially depends on the induction of CD4+CD39+FoxP3+ Treg cells. G-MSCs provide a promising approach for the treatment of autoimmune diseases. Copyright © 2013 by the American College of Rheumatology.5'-NucleotidaseAnimalsAntigensCDApyraseArthritisExperimentalCell DifferentiationFemaleGingivaGPI-Linked ProteinsHumansImmunotherapyAdoptiveMesenchymal Stem Cell TransplantationMesenchymal Stromal CellsMiceMiceInbred DBASignal TransductionT-LymphocytesRegulatoryTh1 CellsTh17 Cells5' nucleotidasebeta1 integrinCD25 antibodyCD39 antigencollagen type 2endoglinFreund adjuvantgamma interferonHermes antigeninterleukin 10interleukin 13interleukin 17interleukin 4interleukin 5lymphocyte antibodytranscription factor FOXP3tumor necrosis factor alphaunclassified drugadoptive transferanimal experimentanimal modelanimal tissuearthritisarticleCD4+ CD39+ FoxP3+ T lymphocytecontrolled studycytokine productiondisease severitydown regulationfemalegingivagingiva derived mesenchymal stem cellhistopathologyhumanhuman cellin vitro studylymph nodelymphocyte differentiationlymphocyte proliferationmesenchymal stem cellmousenonhumanpriority journalregulatory T lymphocytesignal transductionspleensynovial fluidT cell depletionT lymphocyteTh1 cellTh17 cellDentistryPeriodontics and PeriodontologyArticle