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Aging (Albany NY). 2016 Aug;8(8):1670-89. doi: 10.18632/aging.101000.

BMI1 inhibits senescence and enhances the immunomodulatory properties of human mesenchymal stem cells via the direct suppression of MKP-1/DUSP1.

Lee JY1,2, Yu KR1,2,3, Kim HS4,5, Kang I1,2, Kim JJ1,2, Lee BC1,2, Choi SW1,2, Shin JH1,2, Seo Y1,2, Kang KS1,2.

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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.
Pusan National University School of Medicine, Busan 49241, South Korea.
Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea.


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.


BMI1; Hypoxia; MKP-1; aging; hMSCs; immunomodulation

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