AGE

, Volume 35, Issue 5, pp 1545–1557

Anti-aging effects of vitamin C on human pluripotent stem cell-derived cardiomyocytes

  • Yoon Young Kim
  • Seung-Yup Ku
  • Yul Huh
  • Hung-Ching Liu
  • Seok Hyun Kim
  • Young Min Choi
  • Shin Yong Moon
Article

Abstract

Human pluripotent stem cells (hPSCs) have arisen as a source of cells for biomedical research due to their developmental potential. Stem cells possess the promise of providing clinicians with novel treatments for disease as well as allowing researchers to generate human-specific cellular metabolism models. Aging is a natural process of living organisms, yet aging in human heart cells is difficult to study due to the ethical considerations regarding human experimentation as well as a current lack of alternative experimental models. hPSC-derived cardiomyocytes (CMs) bear a resemblance to human cardiac cells and thus hPSC-derived CMs are considered to be a viable alternative model to study human heart cell aging. In this study, we used hPSC-derived CMs as an in vitro aging model. We generated cardiomyocytes from hPSCs and demonstrated the process of aging in both human embryonic stem cell (hESC)- and induced pluripotent stem cell (hiPSC)-derived CMs. Aging in hESC-derived CMs correlated with reduced membrane potential in mitochondria, the accumulation of lipofuscin, a slower beating pattern, and the downregulation of human telomerase RNA (hTR) and cell cycle regulating genes. Interestingly, the expression of hTR in hiPSC-derived CMs was not significantly downregulated, unlike in hESC-derived CMs. In order to delay aging, vitamin C was added to the cultured CMs. When cells were treated with 100 μM of vitamin C for 48 h, anti-aging effects, specifically on the expression of telomere-related genes and their functionality in aging cells, were observed. Taken together, these results suggest that hPSC-derived CMs can be used as a unique human cardiomyocyte aging model in vitro and that vitamin C shows anti-aging effects in this model.

Keywords

Aging Cardiomyocyte Human pluripotent stem cell Vitamin C 

References

  1. Blackburn EH (2001) Switching and signaling at the telomere. Cell 106:661–673PubMedCrossRefGoogle Scholar
  2. Chin MH, Mason MJ, Xie W, Volinia S, Singer M, Peterson C, Ambartsumyan G, Aimiuwu O, Richter L, Zhang J, Khvorostov I, Ott V, Grunstein M, Lavon N, Benvenisty N, Croce CM, Clark AT, Baxter T, Pyle AD, Teitell MA, Pelegrini M, Plath K, Lowry WE (2009) Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5:111–123PubMedCrossRefGoogle Scholar
  3. Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247PubMedCrossRefGoogle Scholar
  4. Goldstein S (1990) Replicative senescence: the human fibroblast comes of age. Science 249:1129–1133PubMedCrossRefGoogle Scholar
  5. Hanna JH, Saha K, Jaenisch R (2010) Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell 143:508–525PubMedCrossRefGoogle Scholar
  6. Hiyama E, Yokoyama T, Tatsumoto N, Hiyama K, Imamura Y, Murakami Y, Kodama T, Piatyszek MA, Shay JW, Matsuura Y (1995) Telomerase activity in gastric cancer. Cancer Res 55:3258–3262PubMedGoogle Scholar
  7. Huffman KE, Levene SD, Tesmer VM, Shay JW, Wright WE (2000) Telomere shortening is proportional to the size of the G-rich telomeric 3′-overhang. J Biol Chem 275:19719–19722PubMedCrossRefGoogle Scholar
  8. Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A, Livne E, Binah O, Itskovitz-Eldor J, Gepstein L (2001) Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest 108:407–414PubMedGoogle Scholar
  9. Kim YY, Ku SY, Jang J, Oh SK, Kim HS, Kim SH, Choi YM, Moon SY (2008) Use of long-term cultured embryoid bodies may enhance cardiomyocyte differentiation by BMP2. Yonsei Med J 49:819–827PubMedCrossRefGoogle Scholar
  10. Kim YY, Ku SY, Liu HC, Cho HJ, Oh SK, Moon SY, Choi YM (2011) Cryopreservation of human embryonic stem cells derived-cardiomyocytes induced by BMP2 in serum-free condition. Reprod Sci 18:252–260PubMedCrossRefGoogle Scholar
  11. Laflamme MA, Murry CE (2005) Regenerating the heart. Nat Biotechnol 23:845–856PubMedCrossRefGoogle Scholar
  12. Luiking YC, Engelen MP, Deutz NE (2010) Regulation of nitric oxide production in health and disease. Curr Opin Clin Nutr Metab Care 13:97–104PubMedCrossRefGoogle Scholar
  13. Mauritz C, Schwanke K, Reppel M, Neef S, Katsirntaki K, Maier L, Nguemo F, Menke S, Haustein M, Hescheler J, Hasenfuss G, Martin U (2008) Generation of functional murine cardiac myocytes from induced pluripotent stem cells. Circulation 118:507–517PubMedCrossRefGoogle Scholar
  14. Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R, van der Heyden M, Opthof T, Pera M, de la Riviere AB, Passier R, Tertoolen L (2003) Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation 107:2733–2740PubMedCrossRefGoogle Scholar
  15. Oh SK, Kim HS, Ahn HJ, Seol HW, Kim YY, Park YB, Yoon CJ, Kim DW, Kim SH, Moon SY (2005a) Derivation and characterization of new human embryonic stem cell lines: SNUhES1, SNUhES2, and SNUhES3. Stem Cells 23:211–219PubMedCrossRefGoogle Scholar
  16. Oh SK, Kim HS, Park YB, Seol HW, Kim YY, Cho MS, Ku SY, Choi YM, Kim DW, Moon SY (2005b) Methods for expansion of human embryonic stem cells. Stem Cells 23:605–609PubMedCrossRefGoogle Scholar
  17. Pera MF, Reubinoff BE, Trounson A (2000) Human embryonic stem cells. J Cell Sci 113:5–10PubMedGoogle Scholar
  18. Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A (2000) Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol 18:399–404PubMedCrossRefGoogle Scholar
  19. Sheydina A, Riordon DR, Boheler KR (2011) Molecular mechanisms of cardiomyocyte aging. Clin Sci 121:315–329PubMedCrossRefGoogle Scholar
  20. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872PubMedCrossRefGoogle Scholar
  21. Terman A, Brunk UT (1998) On the degradability and exocytosis of ceroid/lipofuscin in cultured rat cardiac myocytes. Mech Ageing Dev 100:145–156PubMedCrossRefGoogle Scholar
  22. Terman A, Brunk UT (2005) The aging myocardium: roles of mitochondrial damage and lysosomal degradation. Heart Lung Circ 14:107–114PubMedCrossRefGoogle Scholar
  23. Terman A, Dalen H, Eaton JW, Neuzil J, Brunk UT (2003) Mitochondrial recycling and aging of cardiac myocytes: the role of autophagocytosis. Exp Gerontol 38:863–876PubMedCrossRefGoogle Scholar
  24. Terman A, Dalen H, Eaton JW, Neuzil J, Brunk UT (2004) Aging of cardiac myocytes in culture: oxidative stress, lipofuscin accumulation, and mitochondrial turnover. Ann N Y Acad Sci 1019:70–77PubMedCrossRefGoogle Scholar
  25. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147PubMedCrossRefGoogle Scholar
  26. Yokoo N, Baba S, Kaichi S, Niwa A, Mima T, Doi H, Yamanaka S, Nakahata T, Heike T (2009) The effects of cardioactive drugs on cardiomyocytes derived from human induced pluripotent stem cells. Biochem Biophys Res Commun 387:482–488PubMedCrossRefGoogle Scholar
  27. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920PubMedCrossRefGoogle Scholar
  28. Zhou H, Ma JH, Zhang PH, Luo AT (2006) Vitamin C pretreatment attenuates hypoxia-induced disturbance of sodium currents in guinea pig ventricular myocytes. J Membr Biol 211:81–87PubMedCrossRefGoogle Scholar

Copyright information

© American Aging Association 2012

Authors and Affiliations

  • Yoon Young Kim
    • 1
  • Seung-Yup Ku
    • 1
    • 2
  • Yul Huh
    • 1
  • Hung-Ching Liu
    • 3
  • Seok Hyun Kim
    • 1
    • 2
  • Young Min Choi
    • 1
    • 2
  • Shin Yong Moon
    • 1
    • 2
  1. 1.Institute of Reproductive Medicine and Population, Medical Research CenterSeoul National UniversitySeoulSouth Korea
  2. 2.Department of Obstetrics and Gynecology, College of MedicineSeoul National UniversitySeoulSouth Korea
  3. 3.Center for Reproductive Medicine and InfertilityWeill Cornell Medical CollegeNew YorkUSA

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