Down-Regulation of Multiple Stress Defence Mechanisms During Differentiation of Human Embryonic Stem Cells

¹ Crucible Lab, Institute for Ageing and Health, Newcastle University, International Centre for Life, NE1 3BZ, UK, Henry Wellcome Building for Biogerontology Research, Institute for Ageing and Health, Newcastle University, NE4 6BE, UK
² North East Institute for Stem Cell Research and Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, NE1 3BZ, UK
³ Henry Wellcome Building for Biogerontology Research, Institute for Ageing and Health, Newcastle University, NE4 6BE, UK
⁴ Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK
⁵ North East Institute for Stem Cell Research and Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, NE1 3BZ, UK, Current address: Centro de Investigación Príncipe Felipe, Valencia, Spain

^* To whom correspondence should be addressed. E-mail: gabriele.saretzki{at}ncl.ac.uk.

	Abstract

Evolutionary theory predicts that cellular maintenance, stress defence and DNA repair mechanisms should be most active in germ line cells, including embryonic stem cells that can differentiate into germ line cells, while it would be energetically unfavourable to keep these up in mortal somatic cells. We tested this hypothesis by examining telomere maintenance, oxidative stress generation and genes involved in antioxidant defence and DNA repair during spontaneous differentiation of two human embryonic stem cell lines. Telomerase activity was quickly down regulated 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, while 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.

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