Downregulation of APE1/Ref‐1 Is Involved in the Senescence of Mesenchymal Stem Cells

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‐re...

Full description

Saved in:
Bibliographic Details
Published in:Stem cells (Dayton, Ohio) Ohio), 2009-06, Vol.27 (6), p.1455-1462
Main Authors: Heo, Jun‐Young, Jing, Kaipeng, Song, Kyoung‐Sub, Seo, Kang‐Sik, Park, Ji‐Hoon, Kim, Jong‐Seok, Jung, Yeon‐Joo, Hur, Gang‐Min, Jo, Deog‐Yeon, Kweon, Gi‐Ryang, Yoon, Wan‐Hee, Lim, Kyu, Hwang, Byung‐Doo, Jeon, Byeong Hwa, Park, Jong‐Il
Format: Article
Language:English
Subjects:
APE1/Ref‐1
Blotting, Western
Cell Line
Cellular Senescence - physiology
DNA-(Apurinic or Apyrimidinic Site) Lyase - biosynthesis
Down-Regulation
Flow Cytometry
Gene Expression
Gene Expression Profiling
hBMSCs
Humans
Immunohistochemistry
Mesenchymal Stromal Cells - cytology
Mesenchymal Stromal Cells - metabolism
Microscopy, Confocal
Oxidative Stress - physiology
Reverse Transcriptase Polymerase Chain Reaction
Senescence
Superoxide
Superoxides - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 stress‐induced 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. STEM CELLS 2009;27:1455–1462
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.54