Senescence of mesenchymal stem cells (Review)

Li,Yi; Wu,Qiong; Wang,Yujia; Li,Li; Bu,Hong; Bao,Ji

doi:10.3892/ijmm.2017.2912

Senescence of mesenchymal stem cells (Review)

Authors:
- Yi Li
- Qiong Wu
- Yujia Wang
- Li Li
- Hong Bu
- Ji Bao
View Affiliations

Affiliations: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
Published online on: March 9, 2017 https://doi.org/10.3892/ijmm.2017.2912
Pages: 775-782

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Mesenchymal stem cells (MSCs) have been used in cell-based therapy for various diseases, due to their immunomodulatory and inflammatory effects. However, the function of MSCs is known to decline with age, a process that is called senescence. To date, the process of MSC senescence remains unknown as in-depth understanding of the mechanisms involved in cellular senescence is lacking. First, senescent MSCs are so heterogeneous that not all of them express the same phenotypic markers. In addition, the genes and signaling pathways which regulate this process in MSCs are still unknown. Thus, an understanding of the molecular processes controlling MSC senescence is crucial to determining the drivers and effectors of age-associated MSC dysfunction. Moreover, the proper use of MSCs for clinical application requires a general understanding of the MSC aging process. Furthermore, such knowledge is essential for the development of therapeutic interventions that can slow or reverse age-related degenerative changes to enhance repair processes and maintain healthy function in aging tissues. To further clarify the properties of senescent cells, as well as to present significant findings from studies on the mechanisms of cellular aging, we summarize these biological features in the senescence of MSCs in this scenario. This review summarizes recent advances in our understanding of the markers and differentiation potential indicating MSC senescence, as well as factors affecting MSC senescence with particular emphasis on the roles of oxidative stress, intrinsic changes in telomere shortening, histone deacetylase and DNA methyltransferase, genes and signaling pathways and immunological properties.

View Figures

View References

1	Payushina O, Domaratskaya E and Starostin V: Mesenchymal stem cells: Sources, phenotype, and differentiation potential. Biol Bull. 33:2–18. 2006. View Article : Google Scholar
2	Musina RA, Bekchanova ES and Sukhikh GT: Comparison of mesenchymal stem cells obtained from different human tissues. Bull Exp Biol Med. 139:504–509. 2005. View Article : Google Scholar : PubMed/NCBI
3	Mareschi K, Ferrero I, Rustichelli D, Aschero S, Gammaitoni L, Aglietta M, Madon E and Fagioli F: Expansion of mesenchymal stem cells isolated from pediatric and adult donor bone marrow. J Cell Biochem. 97:744–754. 2006. View Article : Google Scholar
4	Zhang B, Liu R, Shi D, Liu X, Chen Y, Dou X, Zhu X, Lu C, Liang W, Liao L, et al: Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2–dependent regulatory dendritic cell population. Blood. 113:46–57. 2009. View Article : Google Scholar
5	Trivedi P and Hematti P: Derivation and immunological characterization of mesenchymal stromal cells from human embryonic stem cells. Exp Hematol. 36:350–359. 2008.PubMed/NCBI
6	Anzalone R, Lo Iacono M, Corrao S, Magno F, Loria T, Cappello F, Zummo G, Farina F and La Rocca G: New emerging potentials for human Wharton's jelly mesenchymal stem cells: immunological features and hepatocyte-like differentiative capacity. Stem Cells Dev. 19:423–438. 2010. View Article : Google Scholar
7	Francese R and Fiorina P: Immunological and regenerative properties of cord blood stem cells. Clin Immunol. 136:309–322. 2010. View Article : Google Scholar : PubMed/NCBI
8	Patel DM, Shah J and Srivastava AS: Therapeutic potential of mesenchymal stem cells in regenerative medicine. Stem Cells Int. 2013:4962182013. View Article : Google Scholar : PubMed/NCBI
9	Rubin H: Promise and problems in relating cellular senescence in vitro to aging in vivo. Arch Gerontol Geriatr. 34:275–286. 2002. View Article : Google Scholar
10	Digirolamo CM, Stokes D, Colter D, Phinney DG, Class R and Prockop DJ: Propagation and senescence of human marrow stromal cells in culture: A simple colony-forming assay identifies samples with the greatest potential to propagate and differentiate. Br J Haematol. 107:275–281. 1999. View Article : Google Scholar : PubMed/NCBI
11	Campisi J and d'Adda di Fagagna F: Cellular senescence: When bad things happen to good cells. Nat Rev Mol Cell Biol. 8:729–740. 2007. View Article : Google Scholar : PubMed/NCBI
12	Stenderup K, Justesen J, Clausen C and Kassem M: Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone. 33:919–926. 2003. View Article : Google Scholar : PubMed/NCBI
13	Zhou S, Greenberger JS, Epperly MW, Goff JP, Adler C, Leboff MS and Glowacki J: Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts. Aging Cell. 7:335–343. 2008. View Article : Google Scholar : PubMed/NCBI
14	Singh M and Piekorz RP: Senescence-associated lysosomal α-L-fucosidase (SA-α-Fuc): A sensitive and more robust biomarker for cellular senescence beyond SA-β-Gal. Cell Cycle. 12:19962013. View Article : Google Scholar
15	Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop DJ and Horwitz E: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 8:315–317. 2006. View Article : Google Scholar : PubMed/NCBI
16	Yu Y, Park YS, Kim HS, Kim HY, Jin YM, Jung SC, Ryu KH and Jo I: Characterization of long-term in vitro culture-related alterations of human tonsil-derived mesenchymal stem cells: Role for CCN1 in replicative senescence-associated increase in osteogenic differentiation. J Anat. 225:510–518. 2014. View Article : Google Scholar : PubMed/NCBI
17	Simmons PJ and Torok-Storb B: Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1. Blood. 78:55–62. 1991.PubMed/NCBI
18	Jung EM, Kwon O, Kwon KS, Cho YS, Rhee SK, Min JK and Oh DB: Evidences for correlation between the reduced VCAM-1 expression and hyaluronan synthesis during cellular senescence of human mesenchymal stem cells. Biochem Biophys Res Commun. 404:463–469. 2011. View Article : Google Scholar
19	Lv FJ, Tuan RS, Cheung KM and Leung VY: Concise review: The surface markers and identity of human mesenchymal stem cells. Stem Cells. 32:1408–1419. 2014. View Article : Google Scholar : PubMed/NCBI
20	Laschober GT, Brunauer R, Jamnig A, Fehrer C, Greiderer B and Lepperdinger G: Leptin receptor/CD295 is upregulated on primary human mesenchymal stem cells of advancing biological age and distinctly marks the subpopulation of dying cells. Exp Gerontol. 44:57–62. 2009. View Article : Google Scholar
21	Astudillo P, Ríos S, Pastenes L, Pino AM and Rodríguez JP: Increased adipogenesis of osteoporotic humanmesenchymal stem cells (MSCs) characterizes by impaired leptin action. J Cell Biochem. 103:1054–1065. 2008. View Article : Google Scholar
22	Atashi F, Modarressi A and Pepper MS: The role of reactive oxygen species in mesenchymal stem cell adipogenic and osteogenic differentiation: A review. Stem Cells Dev. 24:1150–1163. 2015. View Article : Google Scholar : PubMed/NCBI
23	Xu J, Qian J, Xie X, Lin L, Zou Y, Fu M, Huang Z, Zhang G, Su Y and Ge J: High density lipoprotein protects mesenchymal stem cells from oxidative stress-induced apoptosis via activation of the PI3K/Akt pathway and suppression of reactive oxygen species. Int J Mol Sci. 13:17104–17120. 2012. View Article : Google Scholar
24	Jiang Y, Mishima H, Sakai S, Liu YK, Ohyabu Y and Uemura T: Gene expression analysis of major lineage-defining factors in human bone marrow cells: effect of aging, gender, and age-related disorders. J Orthop Res. 26:910–917. 2008. View Article : Google Scholar : PubMed/NCBI
25	Komori T: Signaling networks in RUNX2-dependent bone development. J Cell Biochem. 112:750–755. 2011. View Article : Google Scholar : PubMed/NCBI
26	Tu B, Peng ZX, Fan QM, Du L, Yan W and Tang TT: Osteosarcoma cells promote the production of pro-tumor cytokines in mesenchymal stem cells by inhibiting their osteogenic differentiation through the TGF-β/Smad2/3 pathway. Exp Cell Res. 320:164–173. 2014. View Article : Google Scholar
27	Xu C, Wang J, Zhu T, Shen Y, Tang X, Fang L and Xu Y: Cross-talking between PPAR and WNT signaling and its regulation in mesenchymal stem cell differentiation. Curr Stem Cell Res Ther. 11:247–254. 2016. View Article : Google Scholar
28	Isidori AM, Strollo F, Morè M, Caprio M, Aversa A, Moretti C, Frajese G, Riondino G and Fabbri A: Leptin and aging: Correlation with endocrine changes in male and female healthy adult populations of different body weights. J Clin Endocrinol Metab. 85:1954–1962. 2000. View Article : Google Scholar : PubMed/NCBI
29	Lee HM, Joo BS, Lee CH, Kim HY, Ock JH and Lee YS: Effect of glucagon-like peptide-1 on the differentiation of adipose-derived stem cells into osteoblasts and adipocytes. J Menopausal Med. 21:93–103. 2015. View Article : Google Scholar : PubMed/NCBI
30	Stringer B, Waddington R, Houghton A, Stone M, Russell G and Foster G: Serum from postmenopausal women directs differentiation of human clonal osteoprogenitor cells from an osteoblastic toward an adipocytic phenotype. Calcif Tissue Int. 80:233–243. 2007. View Article : Google Scholar : PubMed/NCBI
31	Harman D: Aging: a theory based on free radical and radiation chemistry. J Gerontol. 11:298–300. 1956. View Article : Google Scholar : PubMed/NCBI
32	Poyton RO, Ball KA and Castello PR: Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol Metab. 20:332–340. 2009. View Article : Google Scholar : PubMed/NCBI
33	Balaban RS, Nemoto S and Finkel T: Mitochondria, oxidants, and aging. Cell. 120:483–495. 2005. View Article : Google Scholar : PubMed/NCBI
34	Bedard K and Krause K-H: The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev. 87:245–313. 2007. View Article : Google Scholar : PubMed/NCBI
35	Reuter S, Gupta SC, Chaturvedi MM and Aggarwal BB: Oxidative stress, inflammation, and cancer: How are they linked? Free Radic Biol Med. 49:1603–1616. 2010. View Article : Google Scholar : PubMed/NCBI
36	Boutten A, Goven D, Boczkowski J and Bonay M: Oxidative stress targets in pulmonary emphysema: Focus on the Nrf2 pathway. Expert Opin Ther Targets. 14:329–346. 2010. View Article : Google Scholar : PubMed/NCBI
37	Jeong SG and Cho GW: Endogenous ROS levels are increased in replicative senescence in human bone marrow mesenchymal stromal cells. Biochem Biophys Res Commun. 460:971–976. 2015. View Article : Google Scholar : PubMed/NCBI
38	Benameur L, Charif N, Li Y, Stoltz JF and de Isla N: Toward an understanding of mechanism of aging-induced oxidative stress in human mesenchymal stem cells. Biomed Mater Eng. 25(Suppl 1): 41–46. 2015.
39	Stolzing A, Jones E, McGonagle D and Scutt A: Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech Ageing Dev. 129:163–173. 2008. View Article : Google Scholar : PubMed/NCBI
40	Tsai WB, Chung YM, Takahashi Y, Xu Z and Hu MC: Functional interaction between FOXO3a and ATM regulates DNA damage response. Nat Cell Biol. 10:460–467. 2008. View Article : Google Scholar : PubMed/NCBI
41	Milani P, Ambrosi G, Gammoh O, Blandini F and Cereda C: SOD1 and DJ-1 converge at Nrf2 pathway: a clue for antioxidant therapeutic potential in neurodegeneration. Oxid Med Cell Longev. 2013:8367602013. View Article : Google Scholar : PubMed/NCBI
42	Zhang F, Cui J, Liu X, Lv B, Liu X, Xie Z and Yu B: Roles of microRNA-34a targeting SIRT1 in mesenchymal stem cells. Stem Cell Res Ther. 6:1952015. View Article : Google Scholar : PubMed/NCBI
43	Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G, Dobson CM and Stefani M: Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature. 416:507–511. 2002. View Article : Google Scholar : PubMed/NCBI
44	Passos JF, Saretzki G, Ahmed S, Nelson G, Richter T, Peters H, Wappler I, Birket MJ, Harold G, Schaeuble K, et al: Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol. 5:e1102007. View Article : Google Scholar : PubMed/NCBI
45	Hayflick L and Moorhead PS: The serial cultivation of human diploid cell strains. Exp Cell Res. 25:585–621. 1961. View Article : Google Scholar : PubMed/NCBI
46	Hwang ES: Senescence suppressors: Their practical importance in replicative lifespan extension in stem cells. Cell Mol Life Sci. 71:4207–4219. 2014. View Article : Google Scholar : PubMed/NCBI
47	Harley CB, Futcher AB and Greider CW: Telomeres shorten during ageing of human fibroblasts. Nature. 345:458–460. 1990. View Article : Google Scholar : PubMed/NCBI
48	Guillot PV, Gotherstrom C, Chan J, Kurata H and Fisk NM: Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC. Stem Cells. 25:646–654. 2007. View Article : Google Scholar
49	Bonab MM, Alimoghaddam K, Talebian F, Ghaffari SH, Ghavamzadeh A and Nikbin B: Aging of mesenchymal stem cell in vitro. BMC Cell Biol. 7:142006. View Article : Google Scholar : PubMed/NCBI
50	Parsch D, Fellenberg J, Brümmendorf TH, Eschlbeck AM and Richter W: Telomere length and telomerase activity during expansion and differentiation of human mesenchymal stem cells and chondrocytes. J Mol Med (Berl). 82:49–55. 2004. View Article : Google Scholar
51	Baxter MA, Wynn RF, Jowitt SN, Wraith JE, Fairbairn LJ and Bellantuono I: Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. Stem Cells. 22:675–682. 2004. View Article : Google Scholar : PubMed/NCBI
52	Raz V, Vermolen BJ, Garini Y, Onderwater JJ, Mommaas-Kienhuis MA, Koster AJ, Young IT, Tanke H and Dirks RW: The nuclear lamina promotes telomere aggregation and centromere peripheral localization during senescence of human mesenchymal stem cells. J Cell Sci. 121:4018–4028. 2008. View Article : Google Scholar : PubMed/NCBI
53	Masutomi K, Yu EY, Khurts S, Ben-Porath I, Currier JL, Metz GB, Brooks MW, Kaneko S, Murakami S, DeCaprio JA, et al: Telomerase maintains telomere structure in normal human cells. Cell. 114:241–253. 2003. View Article : Google Scholar : PubMed/NCBI
54	Graakjaer J, Christensen R, Kolvraa S and Serakinci N: Mesenchymal stem cells with high telomerase expression do not actively restore their chromosome arm specific telomere length pattern after exposure to ionizing radiation. BMC Mol Biol. 8:492007. View Article : Google Scholar : PubMed/NCBI
55	Ryu E, Hong S, Kang J, Woo J, Park J, Lee J and Seo JS: Identification of senescence-associated genes in human bone marrow mesenchymal stem cells. Biochem Biophys Res Commun. 371:431–436. 2008. View Article : Google Scholar : PubMed/NCBI
56	Serakinci N, Christensen R, Graakjaer J, Cairney CJ, Keith WN, Alsner J, Saretzki G and Kolvraa S: Ectopically hTERT expressing adult human mesenchymal stem cells are less radio-sensitive than their telomerase negative counterpart. Exp Cell Res. 313:1056–1067. 2007. View Article : Google Scholar : PubMed/NCBI
57	Sawada R, Ito T and Tsuchiya T: Changes in expression of genes related to cell proliferation in human mesenchymal stem cells during in vitro culture in comparison with cancer cells. J Artif Organs. 9:179–184. 2006. View Article : Google Scholar : PubMed/NCBI
58	Li H, Xu D, Li J, Berndt MC and Liu JP: Transforming growth factor β suppresses human telomerase reverse transcriptase (hTERT) by Smad3 interactions with c-Myc and the hTERT gene. J Biol Chem. 281:25588–25600. 2006. View Article : Google Scholar : PubMed/NCBI
59	Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S and Wright WE: Extension of life-span by introduction of telomerase into normal human cells. Science. 279:349–352. 1998. View Article : Google Scholar : PubMed/NCBI
60	Sengupta N and Seto E: Regulation of histone deacetylase activities. J Cell Biochem. 93:57–67. 2004. View Article : Google Scholar : PubMed/NCBI
61	Li Z, Liu C, Xie Z, Song P, Zhao RC, Guo L, Liu Z and Wu Y: Epigenetic dysregulation in mesenchymal stem cell aging and spontaneous differentiation. PLoS One. 6:e205262011. View Article : Google Scholar : PubMed/NCBI
62	Jung JW, Lee S, Seo MS, Park SB, Kurtz A, Kang SK and Kang KS: Histone deacetylase controls adult stem cell aging by balancing the expression of polycomb genes and jumonji domain containing 3. Cell Mol Life Sci. 67:1165–1176. 2010. View Article : Google Scholar : PubMed/NCBI
63	Lee S, Jung JW, Park SB, Roh K, Lee SY, Kim JH, Kang SK and Kang KS: Histone deacetylase regulates high mobility group A2-targeting microRNAs in human cord blood-derived multi-potent stem cell aging. Cell Mol Life Sci. 68:325–336. 2011. View Article : Google Scholar
64	Yuan H-F, Zhai C, Yan X-L, Zhao DD, Wang JX, Zeng Q, Chen L, Nan X, He LJ, Li ST, et al: SIRT1 is required for long-term growth of human mesenchymal stem cells. J Mol Med (Berl). 90:389–400. 2012. View Article : Google Scholar
65	Jaenisch R and Bird A: Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat Genet. 33(Suppl): 245–254. 2003. View Article : Google Scholar : PubMed/NCBI
66	Cervoni N and Szyf M: Demethylase activity is directed by histone acetylation. J Biol Chem. 276:40778–40787. 2001. View Article : Google Scholar : PubMed/NCBI
67	So AY, Jung JW, Lee S, Kim HS and Kang KS: DNA methyl-transferase controls stem cell aging by regulating BMI1 and EZH2 through microRNAs. PLoS One. 6:e195032011. View Article : Google Scholar
68	Rayess H, Wang MB and Srivatsan ES: Cellular senescence and tumor suppressor gene p16. Int J Cancer. 130:1715–1725. 2012. View Article : Google Scholar :
69	Shibata KR, Aoyama T, Shima Y, Fukiage K, Otsuka S, Furu M, Kohno Y, Ito K, Fujibayashi S, Neo M, et al: Expression of the p16INK4A gene is associated closely with senescence of human mesenchymal stem cells and is potentially silenced by DNA methylation during in vitro expansion. Stem Cells. 25:2371–2382. 2007. View Article : Google Scholar : PubMed/NCBI
70	Grosschedl R, Giese K and Pagel J: HMG domain proteins: Architectural elements in the assembly of nucleoprotein structures. Trends Genet. 10:94–100. 1994. View Article : Google Scholar : PubMed/NCBI
71	Yu KR, Park SB, Jung JW, Seo MS, Hong IS, Kim HS, Seo Y, Kang TW, Lee JY, Kurtz A, et al: HMGA2 regulates the in vitro aging and proliferation of human umbilical cord blood-derived stromal cells through the mTOR/p70S6K signaling pathway. Stem Cell Res (Amst). 10:156–165. 2013. View Article : Google Scholar
72	Li Y, Nichols MA, Shay JW and Xiong Y: Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res. 54:6078–6082. 1994.PubMed/NCBI
73	Lin SP, Chiu FY, Wang Y, Yen ML, Kao SY and Hung SC: RB maintains quiescence and prevents premature senescence through upregulation of DNMT1 in mesenchymal stromal cells. Stem Cell Rep. 3:975–986. 2014. View Article : Google Scholar
74	Alessio N, Bohn W, Rauchberger V, Rizzolio F, Cipollaro M, Rosemann M, Irmler M, Beckers J, Giordano A and Galderisi U: Silencing of RB1 but not of RB2/P130 induces cellular senescence and impairs the differentiation potential of human mesenchymal stem cells. Cell Mol Life Sci. 70:1637–1651. 2013. View Article : Google Scholar : PubMed/NCBI
75	Galderisi U, Cipollaro M and Giordano A: The retinoblastoma gene is involved in multiple aspects of stem cell biology. Oncogene. 25:5250–5256. 2006. View Article : Google Scholar : PubMed/NCBI
76	Hutchison CJ and Worman HJ: A-type lamins: Guardians of the soma? Nat Cell Biol. 6:1062–1067. 2004. View Article : Google Scholar : PubMed/NCBI
77	Corrigan DP, Kuszczak D, Rusinol AE, Thewke DP, Hrycyna CA, Michaelis S and Sinensky MS: Prelamin A endoproteolytic processing in vitro by recombinant Zmpste24. Biochem J. 387:129–138. 2005. View Article : Google Scholar :
78	Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ, et al: Genomic instability in laminopathy-based premature aging. Nat Med. 11:780–785. 2005. View Article : Google Scholar : PubMed/NCBI
79	Scaffidi P and Misteli T: Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing. Nat Cell Biol. 10:452–459. 2008. View Article : Google Scholar : PubMed/NCBI
80	Yu KR and Kang KS: Aging-related genes in mesenchymal stem cells: A mini-review. Gerontology. 59:557–563. 2013. View Article : Google Scholar : PubMed/NCBI
81	Ksiazek K: A comprehensive review on mesenchymal stem cell growth and senescence. Rejuvenation Res. 12:105–116. 2009. View Article : Google Scholar : PubMed/NCBI
82	Rodier F and Campisi J: Four faces of cellular senescence. J Cell Biol. 192:547–556. 2011. View Article : Google Scholar : PubMed/NCBI
83	Liotta F, Angeli R, Cosmi L, Filì L, Manuelli C, Frosali F, Mazzinghi B, Maggi L, Pasini A, Lisi V, et al: Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells. 26:279–289. 2008. View Article : Google Scholar
84	Trento C and Dazzi F: Mesenchymal stem cells and innate tolerance: Biology and clinical applications. Swiss Med Wkly. 140:w131212010.PubMed/NCBI
85	Barbagallo I, Vanella A, Peterson SJ, Kim DH, Tibullo D, Giallongo C, Vanella L, Parrinello N, Palumbo GA, Di Raimondo F, et al: Overexpression of heme oxygenase-1 increases human osteoblast stem cell differentiation. J Bone Miner Metab. 28:276–288. 2010. View Article : Google Scholar
86	Ito T, Sawada R, Fujiwara Y, Seyama Y and Tsuchiya T: FGF-2 suppresses cellular senescence of human mesenchymal stem cells by down-regulation of TGF-beta2. Biochem Biophys Res Commun. 359:108–114. 2007. View Article : Google Scholar : PubMed/NCBI
87	Wu J, Niu J, Li X, Wang X, Guo Z and Zhang F: TGF-β1 induces senescence of bone marrow mesenchymal stem cells via increase of mitochondrial ROS production. BMC Dev Biol. 14:212014. View Article : Google Scholar
88	Gurung S, Werkmeister JA and Gargett CE: Inhibition of transforming growth factor-β receptor signaling promotes culture expansion of undifferentiated human endometrial mesenchymal stem/stromal cells. Sci Rep. 5:150422015. View Article : Google Scholar
89	Lin TM, Tsai JL, Lin SD, Lai CS and Chang CC: Accelerated growth and prolonged lifespan of adipose tissue-derived human mesenchymal stem cells in a medium using reduced calcium and antioxidants. Stem Cells Dev. 14:92–102. 2005. View Article : Google Scholar : PubMed/NCBI
90	Choi KM, Seo YK, Yoon HH, Song KY, Kwon SY, Lee HS and Park JK: Effect of ascorbic acid on bone marrow-derived mesenchymal stem cell proliferation and differentiation. J Biosci Bioeng. 105:586–594. 2008. View Article : Google Scholar : PubMed/NCBI
91	Su ZY, Shu L, Khor TO, Lee JH, Fuentes F and Kong AN: A perspective on dietary phytochemicals and cancer chemo-prevention: oxidative stress, nrf2, and epigenomics. Top Curr Chem. 329:133–162. 2013. View Article : Google Scholar
92	Takeuchi M, Takeuchi K, Kohara A, Satoh M, Shioda S, Ozawa Y, Ohtani A, Morita K, Hirano T, Terai M, et al: Chromosomal instability in human mesenchymal stem cells immortalized with human papilloma virus E6, E7, and hTERT genes. In Vitro Cell Dev Biol Anim. 43:129–138. 2007. View Article : Google Scholar : PubMed/NCBI
93	Simonsen JL, Rosada C, Serakinci N, Justesen J, Stenderup K, Rattan SI, Jensen TG and Kassem M: Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nat Biotechnol. 20:592–596. 2002. View Article : Google Scholar : PubMed/NCBI
94	Wei F, Qu C, Song T, Ding G, Fan Z, Liu D, Liu Y, Zhang C, Shi S and Wang S: Vitamin C treatment promotes mesenchymal stem cell sheet formation and tissue regeneration by elevating telomerase activity. J Cell Physiol. 227:3216–3224. 2012. View Article : Google Scholar :
95	Gharibi B, Farzadi S, Ghuman M and Hughes FJ: Inhibition of Akt/mTOR attenuates age-related changes in mesenchymal stem cells. Stem Cells. 32:2256–2266. 2014. View Article : Google Scholar : PubMed/NCBI
96	Gu Z, Cao X, Jiang J, Li L, Da Z, Liu H and Cheng C: Upregulation of p16INK4A promotes cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients. Cell Signal. 24:2307–2314. 2012. View Article : Google Scholar : PubMed/NCBI
97	Okada M, Kim HW, Matsu-Ura K, Wang YG, Xu M and Ashraf M: Abrogation of age-induced MicroRNA-195 rejuvenates the senescent mesenchymal stem cells by reactivating telomerase. Stem Cells. 34:148–159. 2016. View Article : Google Scholar :
98	Gharibi B and Hughes FJ: Effects of medium supplements on proliferation, differentiation potential, and in vitro expansion of mesenchymal stem cells. Stem Cells Transl Med. 1:771–782. 2012. View Article : Google Scholar : PubMed/NCBI