Downregulation of multiple stress defense mechanisms during differentiation of human embryonic stem cells

Gabriele Saretzki, Theresia Walter, Stuart Atkinson, João F. Passos, Bettina Bareth, W. Nicol Keith, Rebecca Stewart, Stacey Hoare, Miodrag Stojkovic, Lyle Armstrong, Thomas Von Zglinicki, Majlinda Lako

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197 Scopus citations

Abstract

Evolutionary theory predicts that cellular maintenance, stress defense, and DNA repair mechanisms should be most active in germ line cells, including embryonic stem cells that can differentiate into germ line cells, whereas it would be energetically unfavorable to keep these up in mortal somatic cells. We tested this hypothesis by examining telomere maintenance, oxidative stress generation, and genes involved in antioxidant defense and DNA repair during spontaneous differentiation of two human embryonic stem cell lines. Telomerase activity was quickly downregulated during differentiation, probably due to deacetylation of histones H3 and H4 at the hTERT promoter and deacetylation of histone H3 at hTR promoter. Telomere length decreased accordingly. Mitochondrial superoxide production and cellular levels of reactive oxygen species increased as result of increased mitochondrial biogenesis. The expression of major antioxidant genes was downregulated despite this increased oxidative stress. DNA damage levels increased during differentiation, whereas expression of genes involved in different types of DNA repair decreased. These results confirm earlier data obtained during mouse embryonic stem cell differentiation and are in accordance with evolutionary predictions.

Original languageEnglish (US)
Pages (from-to)455-464
Number of pages10
JournalStem Cells
Volume26
Issue number2
DOIs
StatePublished - Feb 1 2008

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Keywords

  • Antioxidant
  • DNA damage
  • Disposable soma
  • Mitochondria
  • Reactive oxygen species
  • Stem cells
  • Telomerase
  • Telomere

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Saretzki, G., Walter, T., Atkinson, S., Passos, J. F., Bareth, B., Keith, W. N., Stewart, R., Hoare, S., Stojkovic, M., Armstrong, L., Von Zglinicki, T., & Lako, M. (2008). Downregulation of multiple stress defense mechanisms during differentiation of human embryonic stem cells. Stem Cells, 26(2), 455-464. https://doi.org/10.1634/stemcells.2007-0628