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EMBRYONIC STEM CELLS

Downregulation of Multiple Stress Defense Mechanisms During Differentiation of Human Embryonic Stem Cells

^aCrucible Lab, Institute for Ageing and Health, International Centre for Life, and
^bHenry Wellcome Building for Biogerontology Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom;
^cNorth East Institute for Stem Cell Research and
^dInstitute of Human Genetics, International Centre for Life, Newcastle University, Newcastle upon Tyne, United Kingdom;
^eCentre for Oncology and Applied Pharmacology, Cancer Research UK Beatson Laboratories, University of Glasgow, Glasgow, United Kingdom

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

Correspondence: Gabriele Saretzki, Ph.D., Crucible Lab, Institute of Human Genetics, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom. Telephone: 44-241-8813; Fax: 44-241-8810; e-mail: gabriele.saretzki{at}ncl.ac.uk

Received August 3, 2007; accepted for publication November 19, 2007.
First published online in STEM CELLS EXPRESS   November 29, 2007.



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.

Disclosure of potential conflicts of interest is found at the end of this article.

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