Overexpression of soluble RAGE in mesenchymal stem cells enhances their immunoregulatory potential for cellular therapy in autoimmune arthritis

Mesenchymal stem cells (MSCs) are attractive agents for cellular therapy in rheumatoid arthritis (RA). The receptor for advanced glycation end products (RAGE) serves as a pattern recognition receptor for endogenous inflammatory ligands. Soluble RAGE (sRAGE) is a truncated form of RAGE that functions as a decoy and acts as an anti-inflammatory molecule. The aim of this study was to determine whether sRAGE has therapeutic effects and the mechanisms active in sRAGE-overexpressing MSCs (sRAGE-MSCs) in an experimental model of RA. sRAGE-MSCs were generated by DNA transfection of human adipose tissue-derived MSCs (Ad-hMSCs). MSCs showed increased expression of VEGF, IL-1 beta, IL-6, and HMGB-1 under inflammatory conditions. However, sRAGE-MSCs showed significantly lower production of these proinflammatory molecules. Expression of immunomodulatory molecules such as IL-10, TGF-beta, and indoleamine 2, 3-dioxygenase was higher in sRAGE-MSCs than in mock-MSCs. sRAGE-MSCs showed enhanced migration potential. Transplantation of sRAGE-MSCs into arthritic IL-1Ra-knockout mice markedly suppressed inflammatory arthritis, decreased Th17 cells, and reciprocally increased regulatory T cells. The differentiation of IFN-gamma(+) CD4(+) and IL-17(+) CD4(+) cells was inhibited by incubation with sRAGE-MSCs compared with mock-MSCs. These findings suggest that sRAGE overexpression in Ad-hMSCs optimizes their immunoregulatory properties, which may be useful as a novel cellular therapy for RA.