Background/Purpose: Dysfunction of immunology and inflammatory responses is crucial in initiating and promoting bone/cartilage destruction in rheumatic arthritis (RA). Inflamed synovial fibroblast cells (ISFs) are  the most prominent player in both inflammation and joint destruction in RA. ISFs not only produce pro-inflammatory cytokines that promote the differentiation and activation of osteoclasts and bone erosion but also expresses matrix metalloproteinases (MMPs) that contribute to matrix degradation. In addition, ISFs have a tumor-like behavior that directly attaches to articular cartilage and invades the extracellular matrix. Gingiva-derived mesenchymal stem cells (GMSC) are a unique population of mesenchymal stem cells(MSCs) with the intrinsic ability of self-renewal, potential for multilineage differentiation and potent immunoregulatory ability. Our preliminary data and many studies from other groups have demonstrated that infusion of MSCs significantly suppressed the disease development in various animal models of autoimmune diseases including RA model, nonetheless, it is unknown whether GMSC can target ISFs in rheumatoid arthritis.

Methods: To explore whether GMSCs suppress cytokines production of ISFs derived from patients with RA, ISFs were co-cultured with GMSC or control cells with different ratios (1:2-1:50 of GMSCs to ISFs) and the production of the pro-inflammatory factors TNF-α, IL-6, IL-12, IL-18, IL-1β, IL-11, IL-15, monocyte chemoattractant protein (MCP)-1, MMPs as well as anti-inflammatory cytokines IL-10, IL-1R were measured by qPCR or ELISA.  ISFs were also co-cultured with GMSCs for 1-3 days and detected by CCK-8 (proliferation) or crystal violet staining (migration and invasion) to study whether GMSCs inhibit the tumor-like biologic behaviors of ISFs. To determine whether GMSC target ISFs in vivo, GMSC were adoptively transferred into CIA mice and humanized animal model.

Results: Our results showed that GSMC but not control cells significantly inhibited the production of the pro-inflammatory factors and matrix metalloproteinases, as well as proliferation, migration and invasion of ISFs isolated from RA patients in vitro. In line with these results in vitro, infusion of GMSCs reduced the activation of osteoclasts and bone erosion in CIA mice. ISFs isolated from CIA treated with GMSCs showed reduced expression of pro-inflammatory factors and matrix metalloproteinases and suppressed tumor-like biologic behaviors, with lower proliferation, migration and invasion. Moreover, infusion of GMSC markedly controlled the migration and invasion of RA-ISFs in a humanized animal model.  

Conclusion: GMSC target RA-ISFs that implicates GMSC may have a potential promise to treat patients with RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gingival-derived-mesenchymal-stem-cells-alleviate-cartilage-damage-in-collagen-induced-arthritis-via-suppressing-activities-of-inflamed-synovial-fibroblast/