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Wnt/β-catenin signaling induces the aging of mesenchymal stem cells through promoting the ROS production

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Abstract

Recent studies have demonstrated that the Wnt/β-catenin signaling plays an important role in stem cell aging. However, the mechanisms of cell senescence induced by Wnt/β-catenin signaling are still poorly understood. Our preliminary study has indicated that activated Wnt/β-catenin signaling can induce MSC aging. In this study, we reported that the Wnt/β-catenin signaling was a potent activator of reactive oxygen species (ROS) generation in MSCs. After scavenging ROS with N-acetylcysteine, Wnt/β-catenin signaling-induced MSC aging was significantly attenuated and the DNA damage and the expression of p16INK4A, p53, and p21 were reduced in MSCs. These results indicated that the Wnt/β-catenin signaling could induce MSC aging through promoting the intracellular production of ROS, and ROS may be the main mediators of MSC aging induced by excessive activation of Wnt/β-catenin signaling.

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Abbreviations

MSCs:

Mesenchymal stem cells

NAC:

N-acetylcysteine

DCFH-DA:

2′,7′-Dichlorfluorescein-diacetate

SOD:

Superoxide dismutase

MDA:

Malondialdehyde

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

FITC:

Fluorescein isothiocyanate

DAPI:

4′,6-Diamidino-2-phenylindole

References

  1. Wodarz A, Nusse R (1998) Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 14:59–88. doi:10.1146/annurev.cellbio.14.1.59

    Article  PubMed  CAS  Google Scholar 

  2. Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434(7035):843–850. doi:10.1038/nature03319

    Article  PubMed  CAS  Google Scholar 

  3. Scheller M, Huelsken J, Rosenbauer F, Taketo MM, Birchmeier W, Tenen DG, Leutz A (2006) Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation. Nat Immunol 7(10):1037–1047. doi:10.1038/ni1387

    Article  PubMed  CAS  Google Scholar 

  4. Kirstetter P, Anderson K, Porse BT, Jacobsen SE, Nerlov C (2006) Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat Immunol 7(10):1048–1056. doi:10.1038/ni1381

    Article  PubMed  CAS  Google Scholar 

  5. Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, Rando TA (2007) Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317(5839):807–810. doi:10.1126/science.1144090

    Article  PubMed  CAS  Google Scholar 

  6. Damalas A, Kahan S, Shtutman M, Ben-Ze’ev A, Oren M (2001) Deregulated beta-catenin induces a p53- and ARF-dependent growth arrest and cooperates with Ras in transformation. EMBO J 20(17):4912–4922. doi:10.1093/emboj/20.17.4912

    Article  PubMed  CAS  Google Scholar 

  7. Xu M, Yu Q, Subrahmanyam R, Difilippantonio MJ, Ried T, Sen JM (2008) Beta-catenin expression results in p53-independent DNA damage and oncogene-induced senescence in prelymphomagenic thymocytes in vivo. Mol Cell Biol 28(5):1713–1723. doi:10.1128/MCB.01360-07

    Article  PubMed  CAS  Google Scholar 

  8. Mao CD, Hoang P, DiCorleto PE (2001) Lithium inhibits cell cycle progression and induces stabilization of p53 in bovine aortic endothelial cells. J Biol Chem 276(28):26180–26188. doi:10.1074/jbc.M101188200

    Article  PubMed  CAS  Google Scholar 

  9. Marchand A, Atassi F, Gaaya A, Leprince P, Le Feuvre C, Soubrier F, Lompre AM, Nadaud S (2011) The Wnt/beta-catenin pathway is activated during advanced arterial aging in humans. Aging Cell 10(2):220–232. doi:10.1111/j.1474-9726.2010.00661.x

    Article  PubMed  CAS  Google Scholar 

  10. Zhang DY, Wang HJ, Tan YZ (2011) Wnt/beta-catenin signaling induces the aging of mesenchymal stem cells through the DNA damage response and the p53/p21 pathway. PLoS One 6(6):e21397. doi:10.1371/journal.pone.0021397

    Article  PubMed  CAS  Google Scholar 

  11. Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, Malide D, Rovira II, Schimel D, Kuo CJ, Gutkind JS, Hwang PM, Finkel T (2007) Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317(5839):803–806. doi:10.1126/science.1143578

    Article  PubMed  CAS  Google Scholar 

  12. Cooke MS, Evans MD, Dizdaroglu M, Lunec J (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17(10):1195–1214. doi:10.1096/fj.02-0752rev

    Article  PubMed  CAS  Google Scholar 

  13. Maynard S, Schurman SH, Harboe C, de Souza-Pinto NC, Bohr VA (2009) Base excision repair of oxidative DNA damage and association with cancer and aging. Carcinogenesis 30(1):2–10. doi:10.1093/carcin/bgn250

    Article  PubMed  CAS  Google Scholar 

  14. Rodriguez-Vargas JM, Ruiz-Magana MJ, Ruiz–Ruiz C, Majuelos-Melguizo J, Peralta-Leal A, Rodriguez MI, Munoz-Gamez JA, de Almodovar MR, Siles E, Rivas AL, Jaattela M, Oliver FJ (2012) ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy. Cell Res. doi:10.1038/cr.2012.70

    PubMed  Google Scholar 

  15. Wang H, Zhou W, Zheng Z, Zhang P, Tu B, He Q, Zhu WG (2012) The HDAC inhibitor depsipeptide transactivates the p53/p21 pathway by inducing DNA damage. DNA Repair 11(2):146–156. doi:10.1016/j.dnarep.2011.10.014

    Article  PubMed  CAS  Google Scholar 

  16. Inoue T, Kato K, Kato H, Asanoma K, Kuboyama A, Ueoka Y, Yamaguchi S, Ohgami T, Wake N (2009) Level of reactive oxygen species induced by p21Waf1/CIP1 is critical for the determination of cell fate. Cancer Sci 100(7):1275–1283. doi:10.1111/j.1349-7006.2009.01166.x

    Article  PubMed  CAS  Google Scholar 

  17. Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127(3):469–480. doi:10.1016/j.cell.2006.10.018

    Article  PubMed  CAS  Google Scholar 

  18. Yoon JC, Ng A, Kim BH, Bianco A, Xavier RJ, Elledge SJ (2010) Wnt signaling regulates mitochondrial physiology and insulin sensitivity. Genes Dev 24(14):1507–1518. doi:10.1101/gad.1924910

    Article  PubMed  CAS  Google Scholar 

  19. Wang Q, Zou L, Liu W, Hao W, Tashiro S, Onodera S, Ikejima T (2011) Inhibiting NF-kappaB activation and ROS production are involved in the mechanism of silibinin’s protection against D-galactose-induced senescence. Pharmacol Biochem Behav 98(1):140–149. doi:10.1016/j.pbb.2010.12.006

    Article  PubMed  CAS  Google Scholar 

  20. De Boer J, Wang HJ, Van Blitterswijk C (2004) Effects of Wnt signaling on proliferation and differentiation of human mesenchymal stem cells. Tissue Eng 10(3–4):393–401. doi:10.1089/107632704323061753

    Article  PubMed  Google Scholar 

  21. DeCarolis NA, Wharton KA Jr, Eisch AJ (2008) Which way does the Wnt blow? Exploring the duality of canonical Wnt signaling on cellular aging. Bioessays 30(2):102–106. doi:10.1002/bies.20709

    Article  PubMed  CAS  Google Scholar 

  22. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11(3):298–300

    Article  PubMed  CAS  Google Scholar 

  23. Luo Y, Zou P, Zou J, Wang J, Zhou D, Liu L (2011) Autophagy regulates ROS-induced cellular senescence via p21 in a p38 MAPKalpha dependent manner. Exp Gerontol 46(11):860–867. doi:10.1016/j.exger.2011.07.005

    Article  PubMed  CAS  Google Scholar 

  24. Song H, Cha MJ, Song BW, Kim IK, Chang W, Lim S, Choi EJ, Ham O, Lee SY, Chung N, Jang Y, Hwang KC (2010) Reactive oxygen species inhibit adhesion of mesenchymal stem cells implanted into ischemic myocardium via interference of focal adhesion complex. Stem Cells 28(3):555–563. doi:10.1002/stem.302

    PubMed  CAS  Google Scholar 

  25. Kim HJ, Kim KS, Kim SH, Baek SH, Kim HY, Lee C, Kim JR (2009) Induction of cellular senescence by secretory phospholipase A2 in human dermal fibroblasts through an ROS-mediated p53 pathway. J Gerontol Ser A Biol Sci Med Sci 64(3):351–362. doi:10.1093/gerona/gln055

    Article  Google Scholar 

  26. Soberanes S, Gonzalez A, Urich D, Chiarella SE, Radigan KA, Osornio-Vargas A, Joseph J, Kalyanaraman B, Ridge KM, Chandel NS, Mutlu GM, De Vizcaya-Ruiz A, Budinger GR (2012) Particulate matter Air Pollution induces hypermethylation of the p16 promoter Via a mitochondrial ROS-JNK-DNMT1 pathway. Sci Rep 2:275. doi:10.1038/srep00275

    Article  PubMed  Google Scholar 

  27. Takahashi A, Ohtani N, Yamakoshi K, Iida S, Tahara H, Nakayama K, Nakayama KI, Ide T, Saya H, Hara E (2006) Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat Cell Biol 8(11):1291–1297. doi:10.1038/ncb1491

    Article  PubMed  CAS  Google Scholar 

  28. Kajla S, Mondol AS, Nagasawa A, Zhang Y, Kato M, Matsuno K, Yabe-Nishimura C, Kamata T (2012) A crucial role for Nox 1 in redox-dependent regulation of Wnt-beta-catenin signaling. FASEB J 26(5):2049–2059. doi:10.1096/fj.11-196360

    Article  PubMed  CAS  Google Scholar 

  29. Wang X, Mandal AK, Saito H, Pulliam JF, Lee EY, Ke ZJ, Lu J, Ding S, Li L, Shelton BJ, Tucker T, Evers BM, Zhang Z, Shi X (2012) Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/beta-catenin signaling pathway. Toxicology and applied pharmacology. doi:10.1016/j.taap.2012.04.014

    Google Scholar 

  30. Park JW, Kuehn HS, Kim SY, Chung KM, Choi H, Kim M, Kim J, Lee SY, Bae DS, Jin DK, Bae YS (2010) Downregulation of Wnt-mediated ROS generation is causally implicated in leprechaunism. Mol Cells 29(1):63–69. doi:10.1007/s10059-010-0017-z

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge financial support from the Teachers Research Fund of Zhejiang University City College (J-12019, J-12021), the Student Research Fund of Zhejiang University City College (XZ2012562091, X2012562098), the Zhejiang Provincial Foundation of National Science (LQ12H31001), and the Science Research Foundation of the Zhejiang Health Bureau (2012KYA068, 2012KYB066).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Basic Medicine, School of Medicine and Life Sciences, Zhejiang University City College, 51 Huzhou Street, Hangzhou, 310015, People’s Republic of China

    Da-yong Zhang, Yu Pan, Chong Zhang, Bing-xi Yan, Shan-shan Yu, Dong-ling Wu, Meng-meng Shi, Kai Shi, Xin-xiao Cai, Shuang-shuang Zhou, Jun-bo Wang, Jian-ping Pan & Li-huang Zhang

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  1. Da-yong Zhang
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Correspondence to Jun-bo Wang.

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Zhang, Dy., Pan, Y., Zhang, C. et al. Wnt/β-catenin signaling induces the aging of mesenchymal stem cells through promoting the ROS production. Mol Cell Biochem 374, 13–20 (2013). https://doi.org/10.1007/s11010-012-1498-1

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