title: BMI1 inhibits senescence and enhances the immunomodulatory properties of human mesenchymal stem cells via the direct suppression of MKP-1/DUSP1.
abstract: For the application of mesenchymal stem cells (MSCs) as clinical therapeutics, the regulation of cellular aging is important to protect hMSCs from an age-associated decline in their function. In this study, we evaluated the effects of hypoxia on cellular senescence and the immunomodulatory abilities of hUCB-MSCs. Hypoxic-cultured hUCB-MSCs showed enhanced proliferation and had increased immunosuppressive effects on mitogen-induced mononuclear cell proliferation. We found that BMI1, a member of the polycomb repressive complex protein group, showed increased expression in hypoxic-cultured hUCB-MSCs, and the further knock-down of BMI1 in hypoxic cells induced decreased proliferative and immunomodulatory abilities in hUCB-MSCs, along with COX-2/PGE2 down-regulation. Furthermore, the expression of phosphorylated p38 MAP kinase increased in response to the over-expression of BMI1 in normoxic conditions, suggesting that BMI1 regulates the immunomodulatory properties of hUCB-MSCs via p38 MAP kinase-mediated COX-2 expression. More importantly, we identified BMI1 as a direct repressor of MAP kinase phosphatase-1 (MKP-1)/DUSP1, which suppresses p38 MAP kinase activity. In conclusion, our results demonstrate that BMI1 plays a key role in the regulation of the immunomodulatory properties of hUCB-MSCs, and we suggest that these findings might provide a strategy to enhance the functionality of hUCB-MSCs for use in therapeutic applications.
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea.|Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, 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 151-742, South Korea.|Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, 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: 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 151-742, South Korea.|Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, 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 151-742, South Korea.|Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, 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 151-742, South Korea.|Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, 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 151-742, South Korea.|Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, 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 151-742, South Korea.|Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea.
authors.forename: Ji-Hee
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea.|Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, 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 151-742, South Korea.|Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea.
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Kang
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C069077:BMI1 protein, human; D016898:Interferon-alpha; D014409:Tumor Necrosis Factor-alpha; D063150:Polycomb Repressive Complex 1; D048051:p38 Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1
keywords: BMI1; Hypoxia; MKP-1; aging; hMSCs; immunomodulation