title: Therapeutic effects of human gingiva-derived mesenchymal stromal cells on murine contact hypersensitivity via prostaglandin E2-EP3 signaling.
abstract: The 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.
  
  
  
  The 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.
  
  
  
  The 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.
  
  
  
  GMSCs 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.
authors.affiliation: Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing, 100081, People's Republic of China.
authors.forename: Pei
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing, 100081, People's Republic of China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing, 100081, People's Republic of China. gelh0919@126.com.
authors.forename: Lihong
authors.initials: L
authors.lastname: Ge
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003877:Dermatitis, Contact / Q000378:metabolism* / Q000628:therapy*; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D005881:Gingiva / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: D016207:Cytokines; C545648:Ptger3 protein, mouse; D058308:Receptors, Prostaglandin E, EP3 Subtype; C016767:sulprostone; D015232:Dinoprostone
keywords: Contact hypersensitivity; Gingiva-derived mesenchymal stromal cells; Immunomodulation; Local injection; Prostaglandin E2–EP3 pathway; Therapeutic administration