title: PGE2 maintains self-renewal of human adult stem cells via EP2-mediated autocrine signaling and its production is regulated by cell-to-cell contact.
abstract: Mesenchymal stem cells (MSCs) possess unique immunomodulatory abilities. Many studies have elucidated the clinical efficacy and underlying mechanisms of MSCs in immune disorders. Although immunoregulatory factors, such as Prostaglandin E2 (PGE2), and their mechanisms of action on immune cells have been revealed, their effects on MSCs and regulation of their production by the culture environment are less clear. Therefore, we investigated the autocrine effect of PGE2 on human adult stem cells from cord blood or adipose tissue, and the regulation of its production by cell-to-cell contact, followed by the determination of its immunomodulatory properties. MSCs were treated with specific inhibitors to suppress PGE2 secretion, and proliferation was assessed. PGE2 exerted an autocrine regulatory function in MSCs by triggering E-Prostanoid (EP) 2 receptor. Inhibiting PGE2 production led to growth arrest, whereas addition of MSC-derived PGE2 restored proliferation. The level of PGE2 production from an equivalent number of MSCs was down-regulated via gap junctional intercellular communication. This cell contact-mediated decrease in PGE2 secretion down-regulated the suppressive effect of MSCs on immune cells. In conclusion, PGE2 produced by MSCs contributes to maintenance of self-renewal capacity through EP2 in an autocrine manner, and PGE2 secretion is down-regulated by cell-to-cell contact, attenuating its immunomodulatory potency.
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Lee
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.|Pusan National University School of Medicine, Busan 49241, South Korea.|Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea.
authors.forename: Hyung-Sik
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Shin
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.
authors.forename: Insung
authors.initials: I
authors.lastname: Kang
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.
authors.forename: Jae-Jun
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.
authors.forename: Hyun Kyoung
authors.initials: HK
authors.lastname: Kang
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.
authors.forename: Yoojin
authors.initials: Y
authors.lastname: Seo
authors.affiliation: Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.
authors.forename: Seunghee
authors.initials: S
authors.lastname: Lee
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.|Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kyung-Rok
authors.initials: KR
authors.lastname: Yu
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.|Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.
authors.forename: Soon Won
authors.initials: SW
authors.lastname: Choi
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.|Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea.
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Kang
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000328:Adult; D053687:Adult Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D019898:Autocrine Communication / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000502:physiology*; D005312:Fetal Blood / Q000166:cytology; D059585:G1 Phase Cell Cycle Checkpoints; D017629:Gap Junctions / Q000502:physiology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000071876:Prostaglandin-E Synthases / Q000037:antagonists & inhibitors; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; C545644:PTGER2 protein, human; D058307:Receptors, Prostaglandin E, EP2 Subtype; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone