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- Title
Downregulation of APE1/Ref-1 Is Involved in the Senescence of Mesenchymal Stem Cells.
- Authors
Jun-Young Heo; Kaipeng Jing; Kyoung-Sub Song; Kang-Sik Seo; Ji-Hoon Park; Jong-Seok Kim; Yeon-Joo Jung; Gang-Min Hur; Deog-Yeon Jo; Gi-Ryang Kweon; Wan-Hee Yoon; Kyu Lim; Byung-Doo Hwang; Byeong Hwa Jeon; Jong-Il Park
- Abstract
The senescence of human mesenchymal stem cells (hMSCs) causes disruption of tissue and organ maintenance, and is thus an obstacle to stem cell-based therapies for disease. Although some researchers have studied changes in the characteristics of hMSCs (decreases in differentiation ability and self-renewal), comparing young and old ages, the mechanisms of stem cell senescence have not yet been defined. In this study, we developed a growth curve for human bone marrow derived MSCs (hBMSCs) which changes into a hyperbolic state after passage number 7. Senescence associated β-galactosidase (SA β-gal) staining of hBMSCs showed 10% in passage 9 and 45% in passage 11. We detected an increase in endogenous superoxide levels during senescence that correlated with senescence markers (SA β-gal, hyperbolic growth curve). Interestingly, even though endogenous superoxide increased in a replicative senescence model, the expression of APE1/Ref-1, which is sensitive to intracellular redox state, decreased. These effects were confirmed in a stressinduced senescence model by exogenous treatment with H2O2. This change is related to the p53 activity that negatively regulates APE1/Ref-1. p21 expression levels, which represent p53 activity, were transiently increased in passage 9, meaning that they correlated with the expression of APE1/Ref-1. Overexpression of APE1/Ref-1 suppressed superoxide production and decreased SA β-gal in hBMSCs. In conclusion, intracellular superoxide accumulation appears to be the main cause of the senescence of hBMSCs, and overexpression of APE1/Ref-1 can rescue cells from the senescence phenotype. Maintaining characteristics of hBMSCs by regulating intracellular reactive oxygen species production can contribute to tissue regeneration and to improved cell therapy.
- Subjects
STEM cells; CYTOLOGY; OLD age; GENE expression; CELL differentiation; CELLULAR therapy; REACTIVE oxygen species
- Publication
Stem Cells, 2009, Vol 27, Issue 6, p1455
- ISSN
1066-5099
- Publication type
Article
- DOI
10.1002/stem.54