title: A p38 MAPK-mediated alteration of COX-2/PGE2 regulates immunomodulatory properties in human mesenchymal stem cell aging.
abstract: Because human mesenchymal stem cells (hMSC) have profound immunomodulatory effects, many attempts have been made to use hMSCs in preclinical and clinical trials. For hMSCs to be used in therapy, a large population of hMSCs must be generated by in vitro expansion. However, the immunomodulatory changes following the in vitro expansion of hMSCs have not been elucidated. In this study, we evaluated the effect of replicative senescence on the immunomodulatory ability of hMSCs in vitro and in vivo. Late-passage hMSCs showed impaired suppressive effect on mitogen-induced mononuclear cell proliferation. Strikingly, late-passage hMSCs had a significantly compromised protective effect against mouse experimental colitis, which was confirmed by gross and histologic examination. Among the anti-inflammatory cytokines, the production of prostaglandin E2 (PGE2) and the expression of its primary enzyme, cyclooxygenase-2 (COX-2), were profoundly increased by pre-stimulation with interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), and this response was significantly decreased with consecutive passages. We demonstrated that the impaired phosphorylation activity of p38 MAP kinase (p38 MAPK) in late-passage hMSCs led to a compromised immunomodulatory ability through the regulation of COX-2. In conclusion, our data indicate that the immunomodulatory ability of hMSCs gradually declines with consecutive passages via a p38-mediated alteration of COX-2 and PGE2 levels.
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, South Korea; Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
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, South Korea; Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 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, South Korea; Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Biotechnology Incubating Center, Seoul National University, Seoul, 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, South Korea; Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Hong
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, South Korea; Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 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, South Korea; Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
authors.forename: Yoojin
authors.initials: Y
authors.lastname: Seo
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, South Korea; Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 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, South Korea; Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 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, South Korea; Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 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, South Korea; Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Biotechnology Incubating Center, Seoul National University, Seoul, 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, South Korea; Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Korea; Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kurtz
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, South Korea; Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Biotechnology Incubating Center, Seoul National University, Seoul, Korea.
authors.forename: Kwang-Won
authors.initials: KW
authors.lastname: Seo
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, South Korea; Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Kang
mesh_terms: D000818:Animals; D016922:Cellular Senescence; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D019610:Cytoprotection; D016264:Dextran Sulfate; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D056747:Immunomodulation; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000201:enzymology*; D008810:Mice, Inbred C57BL; D010641:Phenotype; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D016264:Dextran Sulfate; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone
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