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Human Molecular Genetics Advance Access originally published online on April 27, 2006
Human Molecular Genetics 2006 15(11):1894-1913; doi:10.1093/hmg/ddl112
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© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited

The role of PI3K/AKT, MAPK/ERK and NF{kappa}ß signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis

Lyle Armstrong1,2,{dagger}, Owen Hughes1,2,{dagger}, Sun Yung1,2, Louise Hyslop1,2, Rebecca Stewart1,2, Ilka Wappler1,2, Heiko Peters1,2, Theresia Walter1,2, Petra Stojkovic1,2,{ddagger}, Jerome Evans2, Miodrag Stojkovic1,2,{ddagger} and Majlinda Lako1,2,*

1Centre for Stem Cell Biology and 2Developmental Genetics, Institute of Human Genetics, University of Newcastle, Newcastle upon Tyne, UK

* To whom correspondence should be addressed at: Centre for Stem Cell Biology and Developmental Genetics, Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, Central Parkways, Newcastle upon Tyne NE1 3BZ, UK. Tel: +44 1912418688; Fax: +44 1912418666; Email: majlinda.lako{at}ncl.ac.uk

Received January 16, 2006; Revised March 11, 2006; Accepted April 11, 2006

Understanding the molecular mechanism by which pluripotency is maintained in human embryonic stem cells (hESC) is important for the development of improved methods to derive, culture and differentiate these into cells of potential therapeutic use. Large-scale transcriptional comparison of the hES-NCL1 line derived from a day 8 embryo with H1 line derived from a day 5 embryo (WiCell Inc.) showed that only 0.52% of the transcripts analysed varied significantly between the two cell lines. This is within the variability range that has been reported when hESC derived from days 5–6 embryos have been compared with each other. This implies that transcriptional differences between the cell lines are likely to reflect their genetic profile rather than the embryonic stage from which they were derived. Bioinformatic analysis of expression changes observed when these cells were induced to differentiate as embryoid bodies suggested that quite a few of the downregulated genes were components of signal transduction networks. Subsequent analysis using western blotting, flow cytometry and antibody arrays implicated components of the PI3K/AKT kinase, MAPK/ERK and NF{kappa}ß pathways and confirmed that these components are decreased upon differentiation. Disruption of these pathways in isolation using specific inhibitors resulted in loss of pluripotency and/or loss of viability suggesting the importance of such signalling pathways in embryonic stem cell maintenance.

{dagger}The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

{ddagger}Present address: Centro de Investigación Príncipe Felipe, Valencia, Spain.


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