PPAR beta/delta-Interfering Peptide Enhanced Mesenchymal Stromal Cell Immunoregulatory Properties

Background. Mesenchymal stem/stromal cells (MSCs) have been widely used for their therapeutic properties in many clinical applications including osteoarthritis. Despite promising preclinical results showing the ability of MSC to reduce the clinical severity of osteoarthritis (OA) in experimental animal models, the benefits of intra-articular injection of MSC in OA patients are limited to the short term. In this regard, it is anticipated that improving the properties of MSC may collectively enhance their long-term beneficial effects on OA. Methods and Results. Recently, we have shown that PPAR beta/delta inhibition using a commercially available antagonist in murine MSC increases their immunoregulatory potential in vitro as well as their therapeutic potential in an experimental murine arthritis model. Here, we relied on an innovative strategy to inhibit PPAR beta/delta:NF-kappa B TF65 subunit interaction in human MSC by designing and synthesizing an interfering peptide, referred to PP11. Through RT-qPCR experiments, we evidenced that the newly synthesized PP11 peptide reduced the expression level of PDK4, a PPAR beta/delta target gene, but did not modify the expression levels of ACOX1 and CPT1A, PPAR alpha target genes, and FABP4, a PPAR gamma target gene compared with untreated human MSC. Moreover, we showed that human MSCs pretreated with PP11 exhibit a significantly higher capacity to inhibit the proliferation of activated PBMC and to decrease the frequency of M1-like macrophages. Conclusions. We designed and synthesized an interfering peptide that potently and specifically blocks PPAR beta/delta activity with concomitant enhancement of MSC immunoregulatory properties.