PPARβ/δ directs the therapeutic potential of mesenchymal stem cells in arthritis

Objectives To define how peroxisome proliferator-activated receptor (PPAR) beta/delta expression level in mesenchymal stem cells (MSCs) could predict and direct both their immunosuppressive and therapeutic properties. PPAR beta/delta interacts with factors such as nuclear factor-kappa B (NF-kappa B) and regulates the expression of molecules including vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1. Since these molecules are critical for MSC function, we investigated the role of PPAR beta/delta on MSC immunosuppressive properties. Methods We either treated human MSCs (hMSCs) with the irreversible PPAR beta/delta antagonist (GSK3787) or derived MSCs from mice deficient for PPAR beta/delta (PPAR beta/delta(-/-) MSCs). We used the collagen-induced arthritis (CIA) as model of immune-mediated disorder and the MSC-immune cell coculture assays. Results Modulation of PPAR beta/delta expression in hMSCs either using GSK3787 or hMSCs from different origin reveals that MSC immunosuppressive potential is inversely correlated with Ppard expression. This was consistent with the higher capacity of PPAR beta/delta(-/-) MSCs to inhibit both the proliferation of T lymphocytes, in vitro, and arthritic development and progression in CIA compared with PPAR beta/delta(+/+) MSCs. When primed with proinflammatory cytokines to exhibit an immunoregulatory phenotype, PPAR beta/delta(-/-) MSCs expressed a higher level of mediators of MSC immunosuppression including VCAM-1, ICAM-1 and nitric oxide (NO) than PPAR beta/delta(+/+) MSCs. The enhanced NO2 production by PPAR beta/delta(-/-) MSCs was due to the increased retention of NF-kappa B p65 subunit on the kappa B elements of the inducible nitric oxide synthase promoter resulting from PPAR beta/delta silencing. Conclusions Our study is the first to show that the inhibition or knockdown of PPAR beta/delta in MSCs primes their immunoregulatory functions. Thus, the regulation of PPAR beta/delta expression provides a new strategy to generate therapeutic MSCs with a stable regulatory phenotype.