Human gingiva-derived mesenchymal stromal cells attenuate contact hypersensitivity via prostaglandin E2-dependent mechanisms.

The immunomodulatory and anti-inflammatory functions of mesenchymal stromal cells (MSCs) have been demonstrated in several autoimmune/inflammatory disease models, but their contribution to the mitigation of contact hypersensitivity (CHS) remains unclear. Here, we report a new immunological approach using human gingiva-derived MSCs (GMSCs) to desensitize and suppress CHS and the underlying mechanisms. Our results showed that systemic infusion of GMSCs before the sensitization and challenge phase dramatically suppress CHS, manifested as a decreased infiltration of dendritic cells (DCs), CD8(+) T cells, T(H)-17 and mast cells (MCs), a suppression of a variety of inflammatory cytokines, and a reciprocal increased infiltration of regulatory T cells and expression of IL-10 at the regional lymph nodes and the allergic contact areas. The GMSC-mediated immunosuppressive effects and mitigation of CHS were significantly abrogated on pretreatment with indomethacin, an inhibitor of cyclooxygenases. Under coculture condition of direct cell-cell contact or via transwell system, GMSCs were capable of direct suppression of differentiation of DCs and phorbol 12-myristate 13-acetate-stimulated activation of MCs, whereas the inhibitory effects were attenuated by indomethacin. Mechanistically, GMSC-induced blockage of de novo synthesis of proinflammatory cytokines by MCs is mediated partly by the tumor necrosis factor-alpha/prostaglandin E(2) (PGE(2)) feedback axis. These results demonstrate that GMSCs are capable of desensitizing allergic contact dermatitis via PGE(2)-dependent mechanisms.

Human gingiva-derived mesenchymal stem cells elicit polarization of m2 macrophages and enhance cutaneous wound healing.

Increasing evidence has supported the important role of mesenchymal stem cells (MSCs) in wound healing, however, the underlying mechanism remains unclear. Recently, we have isolated a unique population of MSCs from human gingiva (GMSCs) with similar stem cell-like properties, immunosuppressive, and anti-inflammatory functions as human bone marrow-derived MSCs (BMSCs). We describe here the interplay between GMSCs and macrophages and the potential relevance in skin wound healing. When cocultured with GMSCs, macrophages acquired an anti-inflammatory M2 phenotype characterized by an increased expression of mannose receptor (MR; CD206) and secretory cytokines interleukin (IL)-10 and IL-6, a suppressed production of tumor necrosis factor (TNF)-α, and decreased ability to induce Th-17 cell expansion. In vivo, we demonstrated that systemically infused GMSCs could home to the wound site in a tight spatial interaction with host macrophages, promoted them toward M2 polarization, and significantly enhanced wound repair. Mechanistically, GMSC treatment mitigated local inflammation mediated by a suppressed infiltration of inflammatory cells and production of IL-6 and TNF-α, and an increased expression of IL-10. The GMSC-induced suppression of TNF-α secretion by macrophages appears to correlate with impaired activation of NFκB p50. These findings provide first evidence that GMSCs are capable to elicit M2 polarization of macrophages, which might contribute to a marked acceleration of wound healing.