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Chemical and Physical Approaches to Extend the Replicative and Differentiation Potential of Stem Cells

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Abstract

Cell therapies using mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) are increasing in regenerative medicine, with applications to a growing number of aging-associated dysfunctions and degenerations. For successful therapies, a certain mass of cells is needed, requiring extensive ex vivo expansion of the cells. However, the proliferation of both MSCs and EPCs is limited as a result of telomere shortening-induced senescence. As cells approach senescence, their proliferation slows down and differentiation potential decreases. Therefore, ways to delay senescence and extend the replicative lifespan these cells are needed. Certain proteins and pathways play key roles in determining the replicative lifespan by regulating ROS generation, damage accumulation, or telomere shortening. And, their agonists and gene activators exert positive effects on lifespan. In many of the treatments, importantly, the lifespan is extended with the retention of differentiation potential. Furthermore, certain culture conditions, including the use of specific atmospheric conditions and culture substrates, exert positive effects on not only the proliferation rate, but also the extent of proliferation and differentiation potential as well as lineage determination. These strategies and known underlying mechanisms are introduced in this review, with an evaluation of their pros and cons in order to facilitate safe and effective MSC expansion ex vivo.

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Abbreviations

MSC:

Mesenchymal stem cell

EPC:

Endothelial progenitor cell

ROS:

Reactive oxygen species

HO-1:

Heme oxygenase-1

PPAR:

Peroxisome proliferator-activated receptor

SOD:

Superoxide dismutase

ECM:

Extracellular matrix

PL:

Platelet lysate

FBS:

Fetal bovine serum

References

  1. Fibbe, W. E., Nauta, A. J., & Roelofs, H. (2007). Modulation of immune responses by mesenchymal stem cells. Annals of the New York Academy of Sciences, 1106, 272–278.

    Article  CAS  PubMed  Google Scholar 

  2. Xu, J. Y., Lee, Y. K., Wang, Y., et al. (2014). Therapeutic application of endothelial progenitor cells for treatment of cardiovascular diseases. Current Stem Cell Research & Therapy, 9(5), 401–414.

    Article  CAS  Google Scholar 

  3. Miura, Y. (2016). Human bone marrow mesenchymal stromal/stem cells: current clinical applications and potential for hematology. International Journal of Hematology, 103(2), 122–128.

    Article  CAS  PubMed  Google Scholar 

  4. Campisi, J., Kim, S. H., Lim, C. S., et al. (2001). Cellular senescence, cancer and aging: the telomere connection. Experimental Gerontology, 36(10), 1619–1637.

    Article  CAS  PubMed  Google Scholar 

  5. Bruder, S. P., Jaiswal, N., & Haynesworth, S. E. (1997). Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation. Journal of Cellular Biochemistry, 64(2), 278–294.

    Article  CAS  PubMed  Google Scholar 

  6. Banfi, A., Muraglia, A., Dozin, B., et al. (2000). Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stromal cells: implications for their use in cell therapy. Experimental Hematology, 28(6), 707–715.

    Article  CAS  PubMed  Google Scholar 

  7. Stenderup, K., Justesen, J., Clausen, C., et al. (2003). Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone, 33(6), 919–926.

    Article  PubMed  Google Scholar 

  8. Rombouts, W. J., & Ploemacher, R. E. (2003). Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia, 17(1), 160–170.

    Article  CAS  PubMed  Google Scholar 

  9. Tokalov, S. V., Gruener, S., Schindler, S., et al. (2007). A number of bone marrow mesenchymal stem cells but neither phenotype nor differentiation capacities changes with age of rats. Molecules and Cells, 24(2), 255–260.

    CAS  PubMed  Google Scholar 

  10. Brohlin, M., Kingham, P. J., Novikova, L. N., et al. (2012). Aging effect on neurotrophic activity of human mesenchymal stem cells. PLoS One, 7(9), e45052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Erickson, I. E., van Veen, S. C., Sengupta, S., et al. (2011). Cartilage matrix formation by bovine mesenchymal stem cells in three-dimensional culture is age-dependent. Clinical Orthopaedics and Related Research, 469(10), 2744–2753.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Stolzing, A., Jones, E., McGonagle, D., et al. (2008). Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mechanisms of Ageing and Development, 129(3), 163–173.

    Article  CAS  PubMed  Google Scholar 

  13. Janzen, V., Forkert, R., Fleming, H. E., et al. (2006). Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature, 443(7110), 421–426.

    CAS  PubMed  Google Scholar 

  14. Efimenko, A., Dzhoyashvili, N., Kalinina, N., et al. (2014). Adipose-derived mesenchymal stromal cells from aged patients with coronary artery disease keep mesenchymal stromal cell properties but exhibit characteristics of aging and have impaired angiogenic potential. Stem Cells Translational Medicine, 3(1), 32–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Reitinger, S., Schimke, M., Klepsch, S., et al. (2015). Systemic impact molds mesenchymal stromal/stem cell aging. Transfusion and Apheresis Science, 52(3), 285–289.

    Article  PubMed  Google Scholar 

  16. Rattan, S. I., & Clark, B. F. (1994). Kinetin delays the onset of ageing characteristics in human fibroblasts. Biochemical and Biophysical Research Communications, 201(2), 665–672.

    Article  CAS  PubMed  Google Scholar 

  17. McFarland, G. A., & Holliday, R. (1994). Retardation of the senescence of cultured human diploid fibroblasts by carnosine. Experimental Cell Research, 212(2), 167–175.

    Article  CAS  PubMed  Google Scholar 

  18. Hwang, E. S. (2014). Senescence suppressors: their practical importance in replicative lifespan extension in stem cells. Cellular and Molecular Life Sciences, 71(21), 4207–4219.

    Article  CAS  PubMed  Google Scholar 

  19. Shay, J., Wright, W., & Werbin, H. (1993). Loss of telomeric DNA during aging may predispose cells to cancer (review). International Journal of Oncology, 3(4), 559–563.

    CAS  PubMed  Google Scholar 

  20. Yudoh, K., Matsuno, H., Nakazawa, F., et al. (2001). Reconstituting telomerase activity using the telomerase catalytic subunit prevents the telomere shorting and replicative senescence in human osteoblasts. Journal of Bone and Mineral Research, 16(8), 1453–1464.

    Article  CAS  PubMed  Google Scholar 

  21. Bocker, W., Yin, Z., Drosse, I., et al. (2008). Introducing a single-cell-derived human mesenchymal stem cell line expressing hTERT after lentiviral gene transfer. Journal of Cellular and Molecular Medicine, 12(4), 1347–1359.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Murasawa, S., Llevadot, J., Silver, M., et al. (2002). Constitutive human telomerase reverse transcriptase expression enhances regenerative properties of endothelial progenitor cells. Circulation, 106(9), 1133–1139.

    Article  CAS  PubMed  Google Scholar 

  23. Shi, S., Gronthos, S., Chen, S., et al. (2002). Bone formation by human postnatal bone marrow stromal stem cells is enhanced by telomerase expression. Nature Biotechnology, 20(6), 587–591.

    Article  CAS  PubMed  Google Scholar 

  24. Simonsen, J. L., Rosada, C., Serakinci, N., et al. (2002). Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nature Biotechnology, 20(6), 592–596.

    Article  CAS  PubMed  Google Scholar 

  25. Dai F, Yang S, Zhang F, et al. (2014). hTERT- and hCTLA4Ig-expressing human bone marrow-derived mesenchymal stem cells: in vitro and in vivo characterization and osteogenic differentiation. Journal of Tissue Engineering and Regenerative Medicine. doi:10.1002/term.1924.

  26. Abdallah, B. M., Haack-Sorensen, M., Burns, J. S., et al. (2005). Maintenance of differentiation potential of human bone marrow mesenchymal stem cells immortalized by human telomerase reverse transcriptase gene despite [corrected] extensive proliferation. Biochemical and Biophysical Research Communications, 326(3), 527–538.

    Article  CAS  PubMed  Google Scholar 

  27. Liang, X. J., Chen, X. J., Yang, D. H., et al. (2012). Differentiation of human umbilical cord mesenchymal stem cells into hepatocyte-like cells by hTERT gene transfection in vitro. Cell Biology International, 36(2), 215–221.

    Article  CAS  PubMed  Google Scholar 

  28. Serakinci, N., Guldberg, P., Burns, J. S., et al. (2004). Adult human mesenchymal stem cell as a target for neoplastic transformation. Oncogene, 23(29), 5095–5098.

    Article  CAS  PubMed  Google Scholar 

  29. Piper, S. L., Wang, M., Yamamoto, A., et al. (2012). Inducible immortality in hTERT-human mesenchymal stem cells. Journal of Orthopaedic Research, 30(12), 1879–1885.

    Article  CAS  PubMed  Google Scholar 

  30. Xia, L., Wang, X. X., Hu, X. S., et al. (2008). Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanisms. British Journal of Pharmacology, 155(3), 387–394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang, X. B., Zhu, L., Huang, J., et al. (2011). Resveratrol-induced augmentation of telomerase activity delays senescence of endothelial progenitor cells. Chinese Medical Journal, 124(24), 4310–4315.

    CAS  PubMed  Google Scholar 

  32. Pearce, V. P., Sherrell, J., Lou, Z., et al. (2008). Immortalization of epithelial progenitor cells mediated by resveratrol. Oncogene, 27(17), 2365–2374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tichon, A., Eitan, E., Kurkalli, B. G., et al. (2013). Oxidative stress protection by novel telomerase activators in mesenchymal stem cells derived from healthy and diseased individuals. Current Molecular Medicine, 13(6), 1010–1022.

    Article  CAS  PubMed  Google Scholar 

  34. Cuervo, A. M., Bergamini, E., Brunk, U. T., Droge, W., Ffrench, M., & Terman, A. (2005). Autophagy and aging: the importance of maintaining “clean” cells. Autophagy, 1, 131–140.

    Article  PubMed  Google Scholar 

  35. Rubinsztein, D. C., Marino, G., & Kroemer, G. (2011). Autophagy and aging. Cell, 146, 682–695.

    Article  CAS  PubMed  Google Scholar 

  36. Brunk, U. T., & Terman, A. (2002). The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. European Journal of Biochemistry, 269(8), 1996–2002.

    Article  CAS  PubMed  Google Scholar 

  37. Lipinski, M. M., Zheng, B., Lu, T., Yan, Z., Py, B. F., Ng, A., et al. (2010). Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 107, 14164–14169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lapierre, L. R., Kumsta, C., Sandri, M., Ballabio, A., & Hansen, M. (2015). Transcriptional and epigenetic regulation of autophagy in aging. Autophagy, 11, 867–880.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Lin, J. R., Shen, W. L., Yan, C., & Gao, P. J. (2015). Downregulation of dynamin-related protein 1 contributes to impaired autophagic flux and angiogenic function in senescent endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 35, 1413–1422.

    Article  CAS  PubMed  Google Scholar 

  40. He, B., Lu, N., & Zhou, Z. (2009). Cellular and nuclear degradation during apoptosis. Current Opinion in Cell Biology, 21(6), 900–912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Noda, T., & Ohsumi, Y. (1998). Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. Journal of Biological Chemistry, 273(7), 3963–3966.

    Article  CAS  PubMed  Google Scholar 

  42. Jozwiak, J., Jozwiak, S., Grzela, T., et al. (2005). Positive and negative regulation of TSC2 activity and its effects on downstream effectors of the mTOR pathway. Neuromolecular Medicine, 7(4), 287–296.

    Article  CAS  PubMed  Google Scholar 

  43. Gharibi, B., Farzadi, S., Ghuman, M., et al. (2014). Inhibition of Akt/mTOR attenuates age-related changes in mesenchymal stem cells. Stem Cells, 32(8), 2256–2266.

    Article  CAS  PubMed  Google Scholar 

  44. Zhang, Q., Yang, Y. J., Wang, H., et al. (2012). Autophagy activation: a novel mechanism of atorvastatin to protect mesenchymal stem cells from hypoxia and serum deprivation via AMP-activated protein kinase/mammalian target of rapamycin pathway. Stem Cells and Development, 21(8), 1321–1332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pataki, A., Muller, K., Green, J. R., et al. (1997). Effects of short-term treatment with the bisphosphonates zoledronate and pamidronate on rat bone: a comparative histomorphometric study on the cancellous bone formed before, during, and after treatment. Anatomical Record, 249(4), 458–468.

    Article  CAS  PubMed  Google Scholar 

  46. Lavu, S., Boss, O., Elliott, P. J., et al. (2008). Sirtuins--novel therapeutic targets to treat age-associated diseases. Nature Reviews Drug Discovery, 7(10), 841–853.

    Article  CAS  PubMed  Google Scholar 

  47. Park, S., Mori, R., & Shimokawa, I. (2013). Do sirtuins promote mammalian longevity? A critical review on its relevance to the longevity effect induced by calorie restriction. Molecules and Cells, 35(6), 474–480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yuan, H. F., Zhai, C., Yan, X. L., et al. (2012). SIRT1 is required for long-term growth of human mesenchymal stem cells. International Journal of Molecular Medicine, 90(4), 389–400.

    Article  CAS  Google Scholar 

  49. Huang, J., Gan, Q., Han, L., et al. (2008). SIRT1 overexpression antagonizes cellular senescence with activated ERK/S6k1 signaling in human diploid fibroblasts. PLoS One, 3(3), e1710.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Langley, E., Pearson, M., Faretta, M., et al. (2002). Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO Journal, 21(10), 2383–2396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Vaziri, H., Dessain, S. K., Ng Eaton, E., et al. (2001). hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell, 107(2), 149–159.

    Article  CAS  PubMed  Google Scholar 

  52. Luo, J., Nikolaev, A. Y., Imai, S., et al. (2001). Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell, 107(2), 137–148.

    Article  CAS  PubMed  Google Scholar 

  53. Lee, I. H., Cao, L., Mostoslavsky, R., et al. (2008). A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proceedings of the National Academy of Sciences of the United States of America, 105(9), 3374–3379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Palacios, J. A., Herranz, D., De Bonis, M. L., et al. (2010). SIRT1 contributes to telomere maintenance and augments global homologous recombination. Journal of Cell Biology, 191(7), 1299–1313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yamashita, S., Ogawa, K., Ikei, T., et al. (2012). SIRT1 prevents replicative senescence of normal human umbilical cord fibroblast through potentiating the transcription of human telomerase reverse transcriptase gene. Biochemical and Biophysical Research Communications, 417(1), 630–634.

    Article  CAS  PubMed  Google Scholar 

  56. Milne, J. C., Lambert, P. D., Schenk, S., et al. (2007). Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature, 450(7170), 712–716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Minor, R. K., Baur, J. A., Gomes, A. P., et al. (2011). SRT1720 improves survival and healthspan of obese mice. Science Reports, 1, 70.

    Google Scholar 

  58. Mitchell, S. J., Martin-Montalvo, A., Mercken, E. M., et al. (2014). The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Reports, 6(5), 836–843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Pacholec, M., Bleasdale, J. E., Chrunyk, B., et al. (2010). SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. Journal of Biological Chemistry, 285(11), 8340–8351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yoon, D. S., Choi, Y., Choi, S. M., et al. (2015). Different effects of resveratrol on early and late passage mesenchymal stem cells through beta-catenin regulation. Biochemical and Biophysical Research Communications, 467(4), 1026–1032.

    Article  CAS  PubMed  Google Scholar 

  61. Tseng, P. C., Hou, S. M., Chen, R. J., et al. (2011). Resveratrol promotes osteogenesis of human mesenchymal stem cells by upregulating RUNX2 gene expression via the SIRT1/FOXO3A axis. Journal of Bone and Mineral Research, 26(10), 2552–2563.

    Article  CAS  PubMed  Google Scholar 

  62. Shakibaei, M., Shayan, P., Busch, F., et al. (2012). Resveratrol mediated modulation of Sirt-1/Runx2 promotes osteogenic differentiation of mesenchymal stem cells: potential role of Runx2 deacetylation. PLoS One, 7(4), e35712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Caldarelli, I., Speranza, M. C., Bencivenga, D., et al. (2015). Resveratrol mimics insulin activity in the adipogenic commitment of human bone marrow mesenchymal stromal cells. International Journal of Biochemistry and Cell Biology, 60, 60–72.

    Article  CAS  PubMed  Google Scholar 

  64. Backesjo, C. M., Li, Y., Lindgren, U., et al. (2009). Activation of Sirt1 decreases adipocyte formation during osteoblast differentiation of mesenchymal stem cells. Cells, Tissues, Organs, 189(1–4), 93–97.

    PubMed  Google Scholar 

  65. Zhou, Y., Zhou, Z., Zhang, W., et al. (2015). SIRT1 inhibits adipogenesis and promotes myogenic differentiation in C3H10T1/2 pluripotent cells by regulating Wnt signaling. Cell & Bioscience, 5, 61.

    Article  Google Scholar 

  66. Xu C, Wang J, Zhu T, et al. (2015). Cross-talking between PPAR and WNT signaling and its regulation in mesenchymal stem cell differentiation. Current Stem Cell Research & Therapy, 11(3), 247–254.

  67. Ross, S. E., Hemati, N., Longo, K. A., et al. (2000). Inhibition of adipogenesis by Wnt signaling. Science, 289(5481), 950–953.

    Article  CAS  PubMed  Google Scholar 

  68. Saunders, L. R., Sharma, A. D., Tawney, J., et al. (2010). miRNAs regulate SIRT1 expression during mouse embryonic stem cell differentiation and in adult mouse tissues. Aging (Albany NY), 2(7), 415–431.

    Article  CAS  Google Scholar 

  69. Sasaki, T., Maier, B., Bartke, A., et al. (2006). Progressive loss of SIRT1 with cell cycle withdrawal. Aging Cell, 5(5), 413–422.

    Article  CAS  PubMed  Google Scholar 

  70. Peng, C. H., Chang, Y. L., Kao, C. L., et al. (2010). SirT1--a sensor for monitoring self-renewal and aging process in retinal stem cells. Sensors, 10(6), 6172–6194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Davies, K. J. (2001). Degradation of oxidized proteins by the 20S proteasome. Biochimie, 83(3–4), 301–310.

    Article  CAS  PubMed  Google Scholar 

  72. Bulteau, A. L., Petropoulos, I., & Friguet, B. (2000). Age-related alterations of proteasome structure and function in aging epidermis. Experimental Gerontology, 35(6–7), 767–777.

    Article  CAS  PubMed  Google Scholar 

  73. Chondrogianni, N., Stratford, F. L., Trougakos, I. P., et al. (2003). Central role of the proteasome in senescence and survival of human fibroblasts: induction of a senescence-like phenotype upon its inhibition and resistance to stress upon its activation. Journal of Biological Chemistry, 278(30), 28026–28037.

    Article  CAS  PubMed  Google Scholar 

  74. Hwang, J. S., Hwang, J. S., Chang, I., et al. (2007). Age-associated decrease in proteasome content and activities in human dermal fibroblasts: restoration of normal level of proteasome subunits reduces aging markers in fibroblasts from elderly persons. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 62(5), 490–499.

    Article  Google Scholar 

  75. Lu, L., Song, H. F., Zhang, W. G., et al. (2012). Potential role of 20S proteasome in maintaining stem cell integrity of human bone marrow stromal cells in prolonged culture expansion. Biochemical and Biophysical Research Communications, 422(1), 121–127.

    Article  CAS  PubMed  Google Scholar 

  76. Lehman, N. L. (2009). The ubiquitin proteasome system in neuropathology. Acta Neuropathologica, 118(3), 329–347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chondrogianni, N., & Gonos, E. S. (2004). Proteasome inhibition induces a senescence-like phenotype in primary human fibroblasts cultures. Biogerontology, 5(1), 55–61.

    Article  CAS  PubMed  Google Scholar 

  78. Kapeta, S., Chondrogianni, N., & Gonos, E. S. (2010). Nuclear erythroid factor 2-mediated proteasome activation delays senescence in human fibroblasts. Journal of Biological Chemistry, 285(11), 8171–8184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ghosh, D., LeVault, K. R., & Brewer, G. J. (2014). Dual-energy precursor and nuclear erythroid-related factor 2 activator treatment additively improve redox glutathione levels and neuron survival in aging and Alzheimer mouse neurons upstream of reactive oxygen species. Neurobiology of Aging, 35(1), 179–190.

    Article  CAS  PubMed  Google Scholar 

  80. Kwak, M. K., Wakabayashi, N., Greenlaw, J. L., et al. (2003). Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Molecular Cell. Biology, 23(23), 8786–8794.

    Article  CAS  Google Scholar 

  81. Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007). Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annual Review of Pharmacology and Toxicology, 47, 89–116.

    Article  CAS  PubMed  Google Scholar 

  82. Chapple, S. J., Siow, R. C., & Mann, G. E. (2012). Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging. International Journal of Biochemistry and Cell Biology, 44(8), 1315–1320.

    Article  CAS  PubMed  Google Scholar 

  83. Gumpricht, E., Dahl, R., Devereaux, M. W., et al. (2005). Licorice compounds glycyrrhizin and 18beta-glycyrrhetinic acid are potent modulators of bile acid-induced cytotoxicity in rat hepatocytes. Journal of Biological Chemistry, 280(11), 10556–10563.

    Article  CAS  PubMed  Google Scholar 

  84. Venugopal, R., & Jaiswal, A. K. (1996). Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proceedings of the National Academy of Sciences of the United States of America, 93(25), 14960–14965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Suzuki, M., Betsuyaku, T., Ito, Y., et al. (2008). Down-regulated NF-E2-related factor 2 in pulmonary macrophages of aged smokers and patients with chronic obstructive pulmonary disease. American Journal of Respiratory Cell and Molecular Biology, 39(6), 673–682.

    Article  CAS  PubMed  Google Scholar 

  86. Droge, W., & Schipper, H. M. (2007). Oxidative stress and aberrant signaling in aging and cognitive decline. Aging Cell, 6(3), 361–370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Milani, P., Ambrosi, G., Gammoh, O., et al. (2013). SOD1 and DJ-1 converge at Nrf2 pathway: a clue for antioxidant therapeutic potential in neurodegeneration. Oxidative Medicine and Cellular Longevity, 2013, 836760.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Hong, F., Freeman, M. L., & Liebler, D. C. (2005). Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chemical Research in Toxicology, 18(12), 1917–1926.

    Article  CAS  PubMed  Google Scholar 

  89. Vincent, A. M., Kato, K., McLean, L. L., et al. (2009). Sensory neurons and schwann cells respond to oxidative stress by increasing antioxidant defense mechanisms. Antioxidants and Redox Signaling, 11(3), 425–438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Na, H. K., & Surh, Y. J. (2008). Modulation of Nrf2-mediated antioxidant and detoxifying enzyme induction by the green tea polyphenol EGCG. Food and Chemical Toxicology, 46(4), 1271–1278.

    Article  CAS  PubMed  Google Scholar 

  91. Su, Z. Y., Shu, L., Khor, T. O., et al. (2013). A perspective on dietary phytochemicals and cancer chemoprevention: oxidative stress, nrf2, and epigenomics. Topics in Current Chemistry, 329, 133–162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Paredes-Gonzalez, X., Fuentes, F., Su, Z. Y., et al. (2014). Apigenin reactivates Nrf2 anti-oxidative stress signaling in mouse skin epidermal JB6 P + cells through epigenetics modifications. The AAPS Journal, 16(4), 727–735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kaidery, N. A., Banerjee, R., Yang, L., et al. (2013). Targeting Nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of Parkinson’s disease. Antioxidants and Redox Signaling, 18(2), 139–157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Neymotin, A., Calingasan, N. Y., Wille, E., et al. (2011). Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis. Free Radical Biology and Medicine, 51(1), 88–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Alam, J., & Cook, J. L. (2003). Transcriptional regulation of the heme oxygenase-1 gene via the stress response element pathway. Current Pharmaceutical Design, 9(30), 2499–2511.

    Article  CAS  PubMed  Google Scholar 

  96. Baranano, D. E., Rao, M., Ferris, C. D., et al. (2002). Biliverdin reductase: a major physiologic cytoprotectant. Proceedings of the National Academy of Sciences of the United States of America, 99(25), 16093–16098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kim, S. Y., & Park, S. C. (2012). Physiological antioxidative network of the bilirubin system in aging and age-related diseases. Frontiers in Pharmacology, 3, 45.

    PubMed  PubMed Central  Google Scholar 

  98. Barbagallo, I., Galvano, F., Frigiola, A., et al. (2013). Potential therapeutic effects of natural heme oxygenase-1 inducers in cardiovascular diseases. Antioxidants and Redox Signaling, 18(5), 507–521.

    Article  CAS  PubMed  Google Scholar 

  99. Kikuchi, G., Yoshida, T., & Noguchi, M. (2005). Heme oxygenase and heme degradation. Biochemical and Biophysical Research Communications, 338(1), 558–567.

    Article  CAS  PubMed  Google Scholar 

  100. Clerigues, V., Guillen, M. I., Castejon, M. A., et al. (2012). Heme oxygenase-1 mediates protective effects on inflammatory, catabolic and senescence responses induced by interleukin-1beta in osteoarthritic osteoblasts. Biochemical Pharmacology, 83(3), 395–405.

    Article  CAS  PubMed  Google Scholar 

  101. Vanella, L., Kim, D. H., Asprinio, D., et al. (2010). HO-1 expression increases mesenchymal stem cell-derived osteoblasts but decreases adipocyte lineage. Bone, 46(1), 236–243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Guillen, M. I., Megias, J., Gomar, F., et al. (2008). Haem oxygenase-1 regulates catabolic and anabolic processes in osteoarthritic chondrocytes. Journal of Pathology, 214(4), 515–522.

    Article  CAS  PubMed  Google Scholar 

  103. Barbagallo, I., Vanella, A., Peterson, S. J., et al. (2010). Overexpression of heme oxygenase-1 increases human osteoblast stem cell differentiation. Journal of Bone and Mineral Metabolism, 28(3), 276–288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Tao, L., Liu, H. R., Gao, E., et al. (2003). Antioxidative, antinitrative, and vasculoprotective effects of a peroxisome proliferator-activated receptor-gamma agonist in hypercholesterolemia. Circulation, 108(22), 2805–2811.

    Article  CAS  PubMed  Google Scholar 

  105. Umeji, K., Umemoto, S., Itoh, S., et al. (2006). Comparative effects of pitavastatin and probucol on oxidative stress, Cu/Zn superoxide dismutase, PPAR-gamma, and aortic stiffness in hypercholesterolemia. American Journal of Physiology - Heart and Circulatory Physiology, 291(5), H2522–H2532.

    Article  CAS  PubMed  Google Scholar 

  106. Chen, J., & Mehta, J. L. (2006). Angiotensin II-mediated oxidative stress and procollagen-1 expression in cardiac fibroblasts: blockade by pravastatin and pioglitazone. American Journal of Physiology - Heart and Circulatory Physiology, 291(4), H1738–H1745.

    Article  CAS  PubMed  Google Scholar 

  107. Lee, Y. H., Lee, N. H., Bhattarai, G., et al. (2010). PPARgamma inhibits inflammatory reaction in oxidative stress induced human diploid fibloblast. Cell Biochemistry and Function, 28(6), 490–496.

    Article  CAS  PubMed  Google Scholar 

  108. Chen, L., Bi, B., Zeng, J., et al. (2015). Rosiglitazone ameliorates senescence-like phenotypes in a cellular photoaging model. Journal of Dermatological Science, 77(3), 173–181.

    Article  CAS  PubMed  Google Scholar 

  109. Yuan, X., Zhang, Z., Gong, K., et al. (2011). Inhibition of reactive oxygen species/extracellular signal-regulated kinases pathway by pioglitazone attenuates advanced glycation end products-induced proliferation of vascular smooth muscle cells in rats. Biological and Pharmaceutical Bulletin, 34(5), 618–623.

    Article  CAS  PubMed  Google Scholar 

  110. Martin, A., Perez-Giron, J. V., Hernanz, R., et al. (2012). Peroxisome proliferator-activated receptor-gamma activation reduces cyclooxygenase-2 expression in vascular smooth muscle cells from hypertensive rats by interfering with oxidative stress. Journal of Hypertension, 30(2), 315–326.

    Article  CAS  PubMed  Google Scholar 

  111. Cheng, H., Qiu, L., Ma, J., et al. (2011). Replicative senescence of human bone marrow and umbilical cord derived mesenchymal stem cells and their differentiation to adipocytes and osteoblasts. Molecular Biology Reports, 38(8), 5161–5168.

    Article  CAS  PubMed  Google Scholar 

  112. Picard, F., & Auwerx, J. (2002). PPAR(gamma) and glucose homeostasis. Annual Review of Nutrition, 22, 167–197.

    Article  CAS  PubMed  Google Scholar 

  113. Viccica, G., Francucci, C. M., & Marcocci, C. (2010). The role of PPARgamma for the osteoblastic differentiation. Journal of Endocrinological Investigation, 33(7 Suppl), 9–12.

    CAS  PubMed  Google Scholar 

  114. Li, X., Pham, H. T., Janesick, A. S., et al. (2012). Triflumizole is an obesogen in mice that acts through peroxisome proliferator activated receptor gamma (PPAR gamma). Environmental Health Perspectives, 120(12), 1720–1726.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Bruedigam, C., Koedam, M., Chiba, H., et al. (2008). Evidence for multiple peroxisome proliferator-activated receptor gamma transcripts in bone: fine-tuning by hormonal regulation and mRNA stability. FEBS Letters, 582(11), 1618–1624.

    Article  CAS  PubMed  Google Scholar 

  116. Case, N., Thomas, J., Xie, Z. H., et al. (2013). Mechanical input restrains PPAR gamma 2 expression and action to preserve mesenchymal stem cell multipotentiality. Bone, 52(1), 454–464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Wassmann, S., Laufs, U., Baumer, A. T., et al. (2001). HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension, 37(6), 1450–1457.

    Article  CAS  PubMed  Google Scholar 

  118. Christ, M., Bauersachs, J., Liebetrau, C., et al. (2002). Glucose increases endothelial-dependent superoxide formation in coronary arteries by NAD(P)H oxidase activation: attenuation by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin. Diabetes, 51(8), 2648–2652.

    Article  CAS  PubMed  Google Scholar 

  119. Wassmann, S., Laufs, U., Muller, K., et al. (2002). Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arteriosclerosis, Thrombosis, and Vascular Biology, 22(2), 300–305.

    Article  CAS  PubMed  Google Scholar 

  120. Mahfouz, M. M., & Kummerow, F. A. (2005). Atorvastatin reduces the plasma lipids and oxidative stress but did not reverse the inhibition of prostacyclin generation by aortas in streptozotocin diabetic rats. Prostaglandins & Other Lipid Mediators, 76(1–4), 59–73.

    Article  CAS  Google Scholar 

  121. Ota, H., Eto, M., Kano, M. R., et al. (2010). Induction of endothelial nitric oxide synthase, SIRT1, and catalase by statins inhibits endothelial senescence through the Akt pathway. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(11), 2205–2211.

    Article  CAS  PubMed  Google Scholar 

  122. Tabuchi, T., Satoh, M., Itoh, T., et al. (2012). MicroRNA-34a regulates the longevity-associated protein SIRT1 in coronary artery disease: effect of statins on SIRT1 and microRNA-34a expression. Clinical Science (London), 123(3), 161–171.

    Article  CAS  Google Scholar 

  123. Bennaceur, K., Atwill, M., Al Zhrany, N., et al. (2014). Atorvastatin induces T cell proliferation by a telomerase reverse transcriptase (TERT) mediated mechanism. Atherosclerosis, 236(2), 312–320.

    Article  CAS  PubMed  Google Scholar 

  124. Assmus, B., Urbich, C., Aicher, A., et al. (2003). HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circulation Research, 92(9), 1049–1055.

    Article  CAS  PubMed  Google Scholar 

  125. Imanishi, T., Hano, T., Sawamura, T., et al. (2004). Oxidized low-density lipoprotein induces endothelial progenitor cell senescence, leading to cellular dysfunction. Clinical and Experimental Pharmacology and Physiology, 31(7), 407–413.

    Article  CAS  PubMed  Google Scholar 

  126. Mohler, E. R., 3rd, Shi, Y., Moore, J., et al. (2009). Diabetes reduces bone marrow and circulating porcine endothelial progenitor cells, an effect ameliorated by atorvastatin and independent of cholesterol. Cytometry. Part A, 75(1), 75–82.

    Article  CAS  Google Scholar 

  127. Liu, Y., Wei, J., Hu, S., et al. (2012). Beneficial effects of statins on endothelial progenitor cells. American Journal of the Medical Sciences, 344(3), 220–226.

    Article  PubMed  Google Scholar 

  128. Spyridopoulos, I., Haendeler, J., Urbich, C., et al. (2004). Statins enhance migratory capacity by upregulation of the telomere repeat-binding factor TRF2 in endothelial progenitor cells. Circulation, 110(19), 3136–3142.

    Article  CAS  PubMed  Google Scholar 

  129. Izadpanah, R., Schachtele, D. J., Pfnur, A. B., et al. (2015). The impact of statins on biological characteristics of stem cells provides a novel explanation for their pleiotropic beneficial and adverse clinical effects. American Journal of Physiology - Cell Physiology, 309(8), C522–C531.

    Article  PubMed  Google Scholar 

  130. Wajid, N., Mehmood, A., Bhatti, F. U., et al. (2013). Lovastatin protects chondrocytes derived from Wharton’s jelly of human cord against hydrogen-peroxide-induced in vitro injury. Cell and Tissue Research, 351(3), 433–443.

    Article  CAS  PubMed  Google Scholar 

  131. Guterres, F. A., Martinez, G. R., Rocha, M. E., et al. (2013). Simvastatin rises reactive oxygen species levels and induces senescence in human melanoma cells by activation of p53/p21 pathway. Experimental Cell Research, 319(19), 2977–2988.

    Article  PubMed  CAS  Google Scholar 

  132. Doucet, C., Ernou, I., Zhang, Y., et al. (2005). Platelet lysates promote mesenchymal stem cell expansion: a safety substitute for animal serum in cell-based therapy applications. Journal of Cellular Physiology, 205(2), 228–236.

    Article  CAS  PubMed  Google Scholar 

  133. Ross, R. (1987). Platelet-derived growth factor. Annual Review of Medicine, 38, 71–79.

    Article  CAS  PubMed  Google Scholar 

  134. Vogel, J. P., Szalay, K., Geiger, F., et al. (2006). Platelet-rich plasma improves expansion of human mesenchymal stem cells and retains differentiation capacity and in vivo bone formation in calcium phosphate ceramics. Platelets, 17(7), 462–469.

    Article  CAS  PubMed  Google Scholar 

  135. Bernardo, M. E., Avanzini, M. A., Perotti, C., et al. (2007). Optimization of in vitro expansion of human multipotent mesenchymal stromal cells for cell-therapy approaches: further insights in the search for a fetal calf serum substitute. Journal of Cellular Physiology, 211(1), 121–130.

    Article  CAS  PubMed  Google Scholar 

  136. Capelli, C., Domenghini, M., Borleri, G., et al. (2007). Human platelet lysate allows expansion and clinical grade production of mesenchymal stromal cells from small samples of bone marrow aspirates or marrow filter washouts. Bone Marrow Transplantation, 40(8), 785–791.

    Article  CAS  PubMed  Google Scholar 

  137. Schallmoser, K., Bartmann, C., Rohde, E., et al. (2007). Human platelet lysate can replace fetal bovine serum for clinical-scale expansion of functional mesenchymal stromal cells. Transfusion, 47(8), 1436–1446.

    Article  CAS  PubMed  Google Scholar 

  138. Xia, W., Li, H., Wang, Z., et al. (2011). Human platelet lysate supports ex vivo expansion and enhances osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. Cell Biology International, 35(6), 639–643.

    Article  CAS  PubMed  Google Scholar 

  139. Lohmann, M., Walenda, G., Hemeda, H., et al. (2012). Donor age of human platelet lysate affects proliferation and differentiation of mesenchymal stem cells. PLoS One, 7(5), e37839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Loffredo, F. S., Steinhauser, M. L., Jay, S. M., et al. (2013). Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell, 153(4), 828–839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Packer, L., & Fuehr, K. (1977). Low oxygen concentration extends the lifespan of cultured human diploid cells. Nature, 267(5610), 423–425.

    Article  CAS  PubMed  Google Scholar 

  142. Saito, H., Hammond, A. T., & Moses, R. E. (1995). The effect of low oxygen tension on the in vitro-replicative life span of human diploid fibroblast cells and their transformed derivatives. Experimental Cell Research, 217(2), 272–279.

    Article  CAS  PubMed  Google Scholar 

  143. Parrinello, S., Samper, E., Krtolica, A., et al. (2003). Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nature Cell Biology, 5(8), 741–747.

    Article  CAS  PubMed  Google Scholar 

  144. Estrada, J. C., Albo, C., Benguria, A., et al. (2012). Culture of human mesenchymal stem cells at low oxygen tension improves growth and genetic stability by activating glycolysis. Cell Death and Differentiation, 19(5), 743–755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Lee, S. H., Lee, J. H., Yoo, S. Y., et al. (2013). Hypoxia inhibits cellular senescence to restore the therapeutic potential of old human endothelial progenitor cells via the hypoxia-inducible factor-1alpha-TWIST-p21 axis. Arteriosclerosis, Thrombosis, and Vascular Biology, 33(10), 2407–2414.

    Article  CAS  PubMed  Google Scholar 

  146. Liu, J., Hao, H., Huang, H., et al. (2015). Hypoxia regulates the therapeutic potential of mesenchymal stem cells through enhanced autophagy. The International Journal of Lower Extremity Wounds, 14(1), 63–72.

    Article  CAS  PubMed  Google Scholar 

  147. Kawasaki, H., Guan, J., & Tamama, K. (2010). Hydrogen gas treatment prolongs replicative lifespan of bone marrow multipotential stromal cells in vitro while preserving differentiation and paracrine potentials. Biochemical and Biophysical Research Communications, 397(3), 608–613.

    Article  CAS  PubMed  Google Scholar 

  148. Ohsawa, I., Ishikawa, M., Takahashi, K., et al. (2007). Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nature Medicine, 13(6), 688–694.

    Article  CAS  PubMed  Google Scholar 

  149. Buchholz, B. M., Kaczorowski, D. J., Sugimoto, R., et al. (2008). Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. American Journal of Transplantation, 8(10), 2015–2024.

    Article  CAS  PubMed  Google Scholar 

  150. Nagatani, K., Wada, K., Takeuchi, S., et al. (2012). Effect of hydrogen gas on the survival rate of mice following global cerebral ischemia. Shock, 37(6), 645–652.

    Article  CAS  PubMed  Google Scholar 

  151. Choi, H. R., Cho, K. A., Kang, H. T., et al. (2011). Restoration of senescent human diploid fibroblasts by modulation of the extracellular matrix. Aging Cell, 10(1), 148–157.

    Article  CAS  PubMed  Google Scholar 

  152. Li, J., Hansen, K. C., Zhang, Y., et al. (2014). Rejuvenation of chondrogenic potential in a young stem cell microenvironment. Biomaterials, 35(2), 642–653.

    Article  CAS  PubMed  Google Scholar 

  153. Sun, C., Liu, X., Qi, L., et al. (2010). Modulation of vascular endothelial cell senescence by integrin beta4. Journal of Cellular Physiology, 225(3), 673–681.

    Article  CAS  PubMed  Google Scholar 

  154. Pioletti, D. P., Takei, H., Lin, T., et al. (2000). The effects of calcium phosphate cement particles on osteoblast functions. Biomaterials, 21(11), 1103–1114.

    Article  CAS  PubMed  Google Scholar 

  155. Lindner, U., Kramer, J., Behrends, J., et al. (2010). Improved proliferation and differentiation capacity of human mesenchymal stromal cells cultured with basement-membrane extracellular matrix proteins. Cytotherapy, 12(8), 992–1005.

    Article  CAS  PubMed  Google Scholar 

  156. Lai, Y., Sun, Y., Skinner, C. M., et al. (2010). Reconstitution of marrow-derived extracellular matrix ex vivo: a robust culture system for expanding large-scale highly functional human mesenchymal stem cells. Stem Cells and Development, 19(7), 1095–1107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Gronthos, S., Simmons, P. J., Graves, S. E., & Robey, P. G. (2001). Integrin-mediated interactions between human bone marrow stromal precursor cells and the extracellular matrix. Bone, 8(2), 174–181.

    Article  Google Scholar 

  158. Hamidouche, Z., Fromigué, O., Ringe, J., et al. (2009). Priming integrin alpha5 promotes human mesenchymal stromal cell osteoblast differentiation and osteogenesis. Proceedings of the National Academy of Sciences of the United States of America, 106(44), 18587–18591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Saidak, Z., Le Henaff, C., Azzi, S., et al. (2015). Wnt/beta-catenin signaling mediates osteoblast differentiation triggered by peptide-induced alpha5beta1 integrin priming in mesenchymal skeletal cells. Journal of Biological Chemistry, 290(11), 6903–6912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Kang, H. T., Lee, H. I., & Hwang, E. S. (2006). Nicotinamide extends replicative lifespan of human cells. Aging Cell, 5(5), 423–436.

    Article  CAS  PubMed  Google Scholar 

  161. Bulavin, D. V., Demidov, O. N., Saito, S., et al. (2002). Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nature Genetics, 31(2), 210–215.

    Article  CAS  PubMed  Google Scholar 

  162. Cha, H., Lowe, J. M., Li, H., et al. (2010). Wip1 directly dephosphorylates gamma-H2AX and attenuates the DNA damage response. Cancer Research, 70(10), 4112–4122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Warren, L. A., & Rossi, D. J. (2009). Stem cells and aging in the hematopoietic system. Mechanisms of Ageing and Development, 130(1–2), 46–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Mukherjee, S., Dudley, J. I., & Das, D. K. (2010). Dose-dependency of resveratrol in providing health benefits. Dose Response, 18(8), 478–500.

    Article  CAS  Google Scholar 

  165. Jiang, H., Shang, X., Wu, H., et al. (2009). Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. Journal of Experimental Therapeutics and Oncology, 8(1), 25–33.

    PubMed  PubMed Central  Google Scholar 

  166. Graham, R. M., Hernandez, F., Puerta, N., et al. (2016). Resveratrol augments ER stress and the cytotoxic effects of glycolytic inhibition in neuroblastoma by downregulating Akt in a mechanism independent of SIRT1. Experimental and Molecular Medicine, 48, e210. doi:10.1038/emm.2015.116.

    Article  CAS  PubMed  Google Scholar 

  167. Selvaraj, S., Sun, Y., Sukumaran, P., & Singh, B. B. (2015). Resveratrol activates autophagic cell death in prostate cancer cells via downregulation of STIM1 and the mTOR pathway. Molecular Carcinogenesis. doi:10.1002/mc.22324.

    PubMed  Google Scholar 

  168. Liu, M. H., Yuan, C., He, J., et al. (2015). Resveratrol protects PC12 cells from high glucose-induced neurotoxicity via PI3K/Akt/FoxO3a pathway. Cellular and Molecular Neurobiology, 35(4), 513–522.

    Article  PubMed  CAS  Google Scholar 

  169. Gurusamy, N., Lekli, I., Mukherjee, S., et al. (2010). Cardioprotection by resveratrol: a novel mechanism via autophagy involving the mTORC2 pathway. Cardiovascular Research, 86(1), 103–112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Jeoung, J. Y., Nam, H. Y., Kwak, J., et al. (2015). A decline in Wnt3a signaling is necessary for mesenchymal stem cells to proceed to replicative senescence. Stem Cells and Development, 24(8), 973–982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Zhang, D. Y., Pan, Y., Zhang, C., et al. (2013). Wnt/beta-catenin signaling induces the aging of mesenchymal stem cells through promoting the ROS production. Molecular and Cellular Biochemistry, 374(1–2), 13–20.

    Article  CAS  PubMed  Google Scholar 

  172. Zhang, D. Y., Wang, H. J., & Tan, Y. Z. (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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work is supported by National Research Foundation of Korea (NRF-2013R1A2A2A01015144).

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  1. Department of Life Science, University of Seoul, Dongdaemun-gu, Seoulsiripdaero 163, Seoul, 02504, Republic of Korea

    Eun Seong Hwang, Jeong Soo Ok & SeonBeom Song

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Hwang, E.S., Ok, J.S. & Song, S. Chemical and Physical Approaches to Extend the Replicative and Differentiation Potential of Stem Cells. Stem Cell Rev and Rep 12, 315–326 (2016). https://doi.org/10.1007/s12015-016-9652-x

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