Abstract
BackgroundThe immunomodulatory and anti-inflammatory functions of human gingiva-derived mesenchymal stromal cells (GMSCs) have been demonstrated in contact hypersensitivity (CHS) models; however, their therapeutic effect during the late phase of CHS has been poor.MethodsThe murine CHS model was induced by applying oxazolone to the ears of mice. Mesenchymal stromal cells were applied via two methods (intravenous or local injection) at three time points: 1 day before sensitization, 1 day before challenge, or 1 h after challenge. Prostaglandin E2 (PGE2) and sulprostone were administered subcutaneously 1 h after challenge.ResultsThe application of GMSCs, bone marrow mesenchymal stem cells, and adipose-derived stem cells all effectively suppressed CHS; however, GMSC treatment exhibited the greatest efficacy. Local injection of GMSCs led to a more marked attenuation of CHS compared with intravenous injection, especially during the late phase of CHS, and this manifested as decreased infiltration of inflammatory cells, suppression of the levels of various proinflammatory cytokines, reconstruction of the disrupted Th1/Th2 balance, and upregulation of regulatory T cells in the allergen contact areas. Pretreatment with indomethacin significantly abrogated the GMSC-mediated immunosuppressive effects, while PGE2 application reversed the effects of indomethacin pretreatment of GMSCs. Moreover, GMSC administration promoted the expression of EP3, a prostaglandin E receptor, and the application of sulprostone, an agonist of EP3, significantly attenuated CHS to a similar degree as that of GMSC administration.ConclusionsGMSCs have reproducible and powerful immunomodulatory functions. Local injection of GMSCs is the superior mode for therapeutic application. PGE2–EP3 signaling plays an important role in the immunomodulatory functions of GMSCs in murine CHS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0361-9) contains supplementary material, which is available to authorized users.
Highlights
The immunomodulatory and anti-inflammatory functions of human gingiva-derived mesenchymal stromal cells (GMSCs) have been demonstrated in contact hypersensitivity (CHS) models; their therapeutic effect during the late phase of CHS has been poor
To clarify the role of EP signaling in allergic skin inflammation, this study focused on the interaction between GMSCs and the Prostaglandin E2 (PGE2)–EP pathway in a CHS model
GMSC characterization The population of nonepithelial progenitor cells isolated from normal gingival tissues showed a spindle-shaped, fibroblast-like morphology (Fig. 1a), colony-forming abilities (Fig. 1e), adherence to plastic, and multilineage differentiation potency, including adipogenesis (Fig. 1b), osteogenesis (Fig. 1c), and chondrogenesis, which is characterized by specific collagen II staining (Fig. 1d)
Summary
The immunomodulatory and anti-inflammatory functions of human gingiva-derived mesenchymal stromal cells (GMSCs) have been demonstrated in contact hypersensitivity (CHS) models; their therapeutic effect during the late phase of CHS has been poor. MSCs, including human bone marrow-derived MSCs (BMSCs) and adipose-derived stem cells (ASCs), have. Recent studies reported that human GMSCs have immunomodulatory properties similar to those of BMSCs, including inhibition of T-cell proliferation and activation, enhancement of Treg generation, and polarization of M2 macrophages [7, 8, 10]. GMSCs can be isolated and obtained readily, maintain a normal karyotype and telomerase activity over long-term culture, display a stable phenotype, and proliferate rapidly in vitro [11, 12]. These characteristics render GMSCs a potential novel immunotherapeutic agent. This study first compared the immunomodulatory capabilities of BMSCs, ASCs, and GMSCs
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