Background/Purpose: Mesenchymal stem cells (MSCs) function as immune regulators in inflammatory conditions. However, it is unclear how to control local inflammation by systemically administered MSCs. We aimed to evaluate the therapeutic effect of human MSCs on inflammatory arthritis and to delineate the underlying mechanisms. 

Methods: Mice with collagen antibody induced arthritis (CAIA) were intraperitoneally injected with human bone marrow-derived MSCs (5 x 10⁶ cells/500 μl of PBS, two times at three-day interval) or control vehicle. The clinical score and histological features of tarsal joints were compared between two groups. The synovial and spleen tissues of CAIA mice were stained with human anti-nuclear antibody (ANA) to confirm the migration of injected human MSCs. After analysis of multiple cytokines on peritoneal cells, migration assay of MSCs was performed in the presence of SDF-1a and/or CCL5. We evaluated the effect of MSCs on induction of regulatory T cells by coculture system in vitro and mRNA profiling in vivo. 

Results: Treatment with human MSCs alleviated the joint inflammation of CAIA mice. The clinical score was consistently lower in mice injected with MSCs compared to control mice. Histological analysis also revealed the conserved articular structure by MSCs. The joints and spleens of CAIA mice treated with human MSCs were positively stained with human ANA, suggesting recruitment of MSCs to inflamed tissues. Peritoneal lavage cells in mice treated with MSCs expressed a higher level of SDF-1a and CCL5, known as chemoattractants. MSCs migrated more easily in the presence of SDF-1a and/or CCL5. The synovia and spleens of CAIA mice treated with MSCs showed the upregulated expression of FOXP3 mRNA, which was supported by enhanced differentiation into regulatory T cells in coculture of CD4+ T cells and MSCs. 

Conclusion: This study suggests that MSCs would directly induce the differentiation of regulatory T cells through migration into inflamed tissues. Systemic administration of MSCs can be a therapeutic option for rheumatoid arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/immune-regulation-by-migrating-mesenchymal-stem-cells-ameliorate-inflammatory-arthritis-in-mice/