A1.4 Inflammatory microenvironment of rheumatoid and osteoarthritic joint affects immunomodulatory activity of adipose-derived mesenchymal stem cells

Abstract

Background and objectives Adipose-derived mesenchymal stem cells (ASCs) have immunomodulatory properties, but their activity is dependent on signals provided by local microenvironment. ASCs administration in rheumatoid arthritis (RA) did not bring consistent results, while in osteoarthritis (OA) it has beneficial effects. It is likely that proinflammatory milieu of rheumatoid joint affects ASCs activity. To test this hypothesis, the function of rheumatoid ASCs (RA-ASCs) and osteoarthritic ASCs (OA-ASCs) isolated from infrapatellar fat pad of the knee joint have been analysed. Materials and methods Infrapatellar fat pads were obtained from 29 RA and 12 OA patients undergoing total knee joint replacement surgery. Then, ASCs were isolated accordingly to routinely applied procedure. ASCs were treated or not with IFNγ or TNF. The expression of indoleamine 2,3-dioxygenase and heme oxygenase 1 mRNA was measured using quantitative PCR, while ASCs secretory potential was assessed by specific ELISAs. Rheumatoid synovial fibroblasts (RA-FLS) or peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured in ASC-conditioned media or co-cultured with ASCs. Next, cytokines secretion and cells proliferation were measured using ELISAs and bromodeoxyuridine/ 3 H-thymidine proliferation assays, respectively. Results RA- and OA-ASCs activity in vitro is comparable, nonetheless some differences in spontaneous secretory activity and heme oxygenase 1 mRNA expression have been observed. Unstimulated RA- and OA-ASCs slightly inhibited PBMCs proliferation and induced IL-10 secretion but increased IL-17A production and failed to suppress release of other proinflammatory factors (TNF, IFNγ, RANTES) by PBMCs. Under TNF stimulation, RA- and OA-ASCs up-regulated IL-6 and MMP-3 secretion in RA-FLS cultures and IL-17A release by PBMCs. ASCs treatment with IFNγ or TNF did not intensify their anti-inflammatory activity. Conclusions Our study demonstrates that immunosuppressive function of RA- and OA-ASCs derived from infrapatellar fat pad is impaired. Possibly, it is due to the localisation of ASCs in the site of inflammation. Moreover, TNF triggers proinflammatory properties of ASCs which indicates that when administered to the rheumatoid joint, ASCs may shift from an anti-inflammatory to proinflammatory phenotype. Acknowledgements This work was supported by the Polish National Science Centre (grant no. 2011/01/N/NZ5/00932) and by the European Union funds (European Social Fund, Human Capital Programme).