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Human Molecular Genetics Advance Access published online on April 27, 2006
Human Molecular Genetics, 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.
Received January 16, 2006
Revised March 11, 2006
Accepted April 11, 2006

Article

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

Lyle Armstrong 1, Owen Hughes 1, Sun Young 1, Louise Hyslop 1, Rebecca Stewart 1, Ilka Wappler 1, Heiko Peters 1, Theresia Walter 1, Petra Stojkovic 2, Jerome Evans 3, Miodrag Stojkovic 2, and Majlinda Lako 4 *

1 Centre for Stem Cell Biology and Developmental Genetics, University of Newcastle, Newcastle upon Tyne, UK; Institute of Human Genetics, University of Newcastle, Newcastle upon Tyne, UK
2 Centre for Stem Cell Biology and Developmental Genetics, University of Newcastle, Newcastle upon Tyne, UK; Institute of Human Genetics, University of Newcastle, Newcastle upon Tyne, UK; Centro de Investigación Príncipe Felipe, Valencia, Spain
3 Institute of Human Genetics, University of Newcastle, Newcastle upon Tyne, UK
4 Centre for Stem Cell Biology and Developmental Genetics, Institute of Human Genetics, University of Newcastle, International Centre for Life, Central Parkways, Newcastle upon Tyne, NE1 3BZ, UK; Institute of Human Genetics, University of Newcastle, Newcastle upon Tyne, UK

* To whom correspondence should be addressed.
Majlinda Lako, E-mail: Majlinda.Lako{at}ncl.ac.uk


  Abstract

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 to 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 day 5-6 embryos have been compared to 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}{beta} 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.


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