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http://dx.doi.org/10.5483/BMBRep.2018.51.7.078

Superoxide dismutase 3 protects mesenchymal stem cells through enhanced autophagy and regulation of FoxO3a trafficking  

Agrahari, Gaurav (Laboratory of Dermato-Immunology, College of Medicine, The Catholic University of Korea)
Sah, Shyam Kishor (Laboratory of Dermato-Immunology, College of Medicine, The Catholic University of Korea)
Kim, Tae-Yoon (Laboratory of Dermato-Immunology, College of Medicine, The Catholic University of Korea)
Publication Information
BMB Reports / v.51, no.7, 2018 , pp. 344-349 More about this Journal
Abstract
Therapeutic applications of mesenchymal stem cells (MSCs) are limited due to their early death within the first few days of transplantation. Therefore, to improve the efficacy of cell-based therapies, it is necessary to manipulate MSCs so that they can resist various stresses imposed by the microenvironment. Moreover, the role of superoxide dismutase 3 (SOD3) in regulating such survival under different stress conditions remain elusive. In this study, we overexpressed SOD3 in MSCs (SOD3-MSCs) and evaluated its effect under serum starvation conditions. Nutritional limitation can decrease the survival rate of transplanted MSCs and thus can reduce their efficacy during therapy. Interestingly, we found that SOD3-MSCs exhibited reduced reactive oxygen species levels and greater survival rates than normal MSCs under serum-deprived conditions. In addition, overexpression of SOD3 attenuated starvation-induced apoptosis with increased autophagy in MSCs. Moreover, we have demonstrated that SOD3 protects MSCs against the negative effects of serum deprivation via modulation of AMP-activated protein kinase/sirtulin 1, extracellular signal-regulated kinase activation, and promoted Forkhead box O3a trafficking to the nucleus. Taken together, these results demonstrate that SOD3 promotes MSCs survival and add further evidence to the concept that SOD3-MSCs may be a potential therapeutic agent with better outcomes than normal MSCs for various diseases involving oxidative stress and compromised MSCs survival during therapy.
Keywords
Apoptosis; Autophagy; Mesenchymal stem cell; Serum starvation; Superoxide dismutase 3;
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1 Biffi A, Montini E, Lorioli L et al (2013) Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341, 1233158   DOI
2 Garbern JC and Lee RT (2013) Cardiac stem cell therapy and the promise of heart regeneration cell. Stem Cell 12, 689-698
3 Greco SJ and Rameshwar P (2012) Mesenchymal stem cells in drug/gene delivery: implications for cell therapy. TherDeliv 3, 997-1004
4 Law S and Chaudhuri S (2013) Mesenchymal stem cell and regenerative medicine: regeneration versus immunomodulatory challenges. Am J Stem Cells 2, 22-38
5 Murphy MB, Moncivais K and Caplan AI (2013) Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med 45, 54   DOI
6 Przybyla LM, Theunissen TW, Jaenisch R and Voldman J (2013) Matrix remodeling maintains embryonic stem cell self-renewal by activating stat3. Stem Cells 31, 1097-1106   DOI
7 Li CJ, Sun LY and Pang CY (2015) Synergistic protection of N-acetylcysteine and ascorbic acid 2-phosphate on human mesenchymal stem cells against mitoptosis, necroptosis and apoptosis. Sci Rep 5, 9819   DOI
8 Saunders A, Faiola F and Wang J (2013) Concise review: pursuing self-renewal and pluripotency with the stem cell factor Nanog. Stem Cells 31, 1227-1236   DOI
9 Haider H and Ashraf M (2010) Preconditioning and stem cell survival. J Cardiovasc Transl Res 3, 89-102   DOI
10 Zhou H, Yang J, Xin T et al (2014) Exendin-4 protects adipose-derived mesenchymal stem cells from apoptosis induced by hydrogen peroxide through the PI3K/Akt-Sfrp2 pathways. Free Radic Biol Med 77, 363-375   DOI
11 Zhang Q, Liu S, Li T et al (2016) Preconditioning of bone marrow mesenchymal stem cells with hydrogen sulfide improves their therapeutic potential. Oncotarget 7, 58089-58104
12 Zhu W, Chen J, Cong X, Hu S and Chen X (2006) Hypoxia and serum deprivation-induced apoptosis in mesenchymal stem cells. Stem Cells 24, 416-425   DOI
13 Sbrana FV, Cortini M, Avnet S, Perut F, Columbaro M, De Milito A and Baldini N (2016) The Role of Autophagy in the Maintenance of Stemness and Differentiation of Mesenchymal Stem Cells. Stem Cell Rev 12, 621-633   DOI
14 Potier E, Ferreira E, Meunier A, Sedel L, Logeart-Avramoglou D and Petite H (2007) Prolonged hypoxia concomitant with serum deprivation induces massive human mesenchymal stem cell death. Tissue Eng 13, 1325-1331   DOI
15 Mizushima N and Klionsky DJ (2007) Protein turnover via autophagy: implications for metabolism. Annu Rev Nutr 27, 19-40   DOI
16 Stolz A, Ernst A and Dikic I (2014) Cargo recognition and trafficking in selective autophagy. Nat Cell Biol 16, 495-501   DOI
17 Gao L, Cen S, Wang P et al (2018) Autophagy Improves the Immunosuppression of $CD4^{+}$ T Cells by Mesenchymal Stem Cells Through Transforming Growth Factor-${\beta}1$. Stem Cells Transl Med 5, 1496-1505
18 Salih DA and Brunet A (2008) FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 20, 126-136   DOI
19 Wang j, Whiteman MW, Lian H et al (2009) A Non-canonical MEK/ERK Signaling Pathway Regulates Autophagy via Regulating Beclin 1. J Biol Chem 284, 21412-21424   DOI
20 Lee SB, Kim JJ, Kim TW, Kim BS, Lee MS and Yoo YD (2010) Serum deprivation induced reactive oxygen species production is mediated by Romo1. Apoptosis 15, 204-218   DOI
21 Rubinsztein DC, Bento CF and Deretic V (2015) Therapeutic targeting of autophagy in neurodegenerative and infectious diseases. J Exp Med 212, 979-990   DOI
22 Zeng W, Xiao J, Zheng G et al (2015) Antioxidant treatment enhances human mesenchymal stem cell anti-stress ability and therapeutic efficacy in an acute liver failure model. Sci Rep 5, 11100   DOI
23 Kim PH, Na SS, Lee B, Kim JH and Cho JY (2015) Stanninocalcin 2 enhances mesenchymal stem cell survival by suppressing oxidaative stress. BMB Rep 48, 702-707   DOI
24 Suh N and Lee Eb (2017) Antioxidant effects of selenocysteine on replicative senescence in human adipose-derived mesenchymal stem cells. BMB Rep 50, 572-577   DOI
25 Van der Vos KE, Eliasson P, Proikas-Cezanne T et al (2012) Modulation of glutamine metabolism by the PI(3)K-PKB-FOXO network regulates autophagy. Nat Cell Biol 14, 829-837   DOI
26 Richard CW, Yongjie W, Zhenyi A et al (2012) Akt-Mediated Regulation of Autophagy and Tumorigenesis Through Beclin 1 Phosphorylation. Science 338, 956-959   DOI
27 Mammucari C, Milan G, Romanello V et al (2007) FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6, 458-471   DOI
28 Mammucari C, Schiaffino S and Sandri M (2008) Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle. Autophagy 4, 524-526   DOI
29 Xiong X, Tao R, Depinho R and Charlie Dong X (2012) The autophagy-related gene 14 (Atg14) is regulated by Forkhead box O transcription factors and circadian rhythms and plays a critical role in hepatic autophagy and lipid metabolism. J Biol Chem 287, 39107-39114   DOI
30 Xu P, Das M, Reilly J and Davis RJ (2011) JNK regulates FoxO-dependent autophagy in neurons. Genes Dev 25, 310-322   DOI
31 Kume S, Uzu T, Horiike K et al (2010) Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J Clin Invest 120, 1043-1055   DOI
32 Laplante M and Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149, 274-293   DOI
33 Kemp K, Hares K, Mallam E, Heesom KJ, Scolding N and Wilkins A (2010) Mesenchymal stem cell-secreted superoxide dismutase promotes cerebellar neuronal survival. J Neurochem 114, 1569-1580   DOI
34 Egan DF, Shackelford DB, Mihaylova MM et al (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456-461   DOI
35 Kim J, Kundu M, Viollet B and Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13, 132-141   DOI
36 An Y, Liu WJ, Xue P et al (2018) Autophagy promotes MSC-mediated vascularization in cutaneous wound healing via regulation of VEGF secretion. Cell Death Dis 9, 58   DOI
37 Wang M, Yang Y, Yang D et at (2009) The immunomodulatory activity of human umbilical cord bloodderived mesenchymal stem cells in vitro. Immunology 126, 220-232   DOI
38 Shinojima N, Yokoyama T, Kondo Y and Kondo S (2007) Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy 3, 635-637   DOI
39 Divya MS, Roshin GE, Divya TS et al (2012) Umbilical cord blood-derived mesenchymal stem cells consist of a unique population of progenitors co-expressing mesenchymal stem cell and neuronal markers capable of instantaneous neuronal differentiation. Stem Cell Res Ther 3, 57   DOI
40 Reddy NP, Vemuri MC and Pallu R (2007) Isolation of stem cells from human umbilical cord blood. Methods Mol Biol 407, 149-163