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Human Molecular Genetics Advance Access published online on September 13, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi345
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© The Author 2005. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oupjournals.org
Received May 26, 2005
Revised August 1, 2005
Accepted September 7, 2005

Article

Cellular Differentiation Hierarchies In Normal And Culture Adapted Human Embryonic Stem Cells

Tariq Enver 1, Shamit Soneji 1, Chirag Joshi 1, John Brown 1, Francisco Iborra 1, Torben Orntoft 2, Thomas Thykjaer 2, Edna Maltby 3, Kath Smith 3, Raed Abu Dawud 4, Mark Jones 4, Maryam Matin 5, Paul Gokhale 4, Jonathan Draper 4, and Peter W. Andrews 4*

1 MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
2 Molecular Diagnostics laboratory, Aarhus University Hospital, Skejby, Denmark
3 North Trent Clinical Cytogenetics Service, Sheffield Children's Trust, Western Bank, Sheffield S10 2TH, UK
4 Centre for Stem Cell Biology, Department of Biomedical Science, University of Sheffield, Sheffield, UK
5 Institute of Biotechnology and Tissue Engineering, Department of Biology, Ferdowsi University of Mashhad, Mashhad, Iran

* To whom correspondence should be addressed.
Peter W. Andrews, E-mail: p.w.andrews{at}sheffield.ac.uk


  Abstract

Human embryonic stem cell (HESC) lines vary in their characteristics and behaviour, not only because they are derived from genetically outbred populations, but also because they may undergo progressive adaptation upon long term culture in vitro. Such adaptation may reflect selection of variants with altered propensity for survival and retention of an undifferentiated phenotype. Elucidating the mechanisms involved will be important for understanding normal self-renewal, commitment to differentiation, and for validating the safety of HESC-based therapy. We have investigated this process of adaptation at the cellular and molecular levels through a comparison of early passage (Normal) and late passage (Adapted) sublines of a single HESC line, H7. To account for spontaneous differentiation that occurs in HESC cultures we sorted cells for SSEA3, which marks undifferentiated HESC. We show that the gene expression programs of the Adapted cells partially reflected their aberrant karyotype but also resulted from a failure in X-inactivation, emphasizing the importance in adaptation of karyotypically-silent epigenetic changes. Based on growth potential, ability to re-initiate ES cultures, and global transcription profiles, we propose a cellular differentiation hierarchy for maintenance cultures of HESC: Normal SSEA3+ cells represent pluripotent stem cells. Normal SSEA3- cells have exited this compartment, but retain multilineage differentiation potential. However, Adapted SSEA3+ and SSEA3- cells co-segregate within the stem cell territory, implying that adaptation reflects an alteration in the balance between self-renewal and differentiation. Since this balance is also an essential feature of cancer, the mechanisms of culture adaptation may mirror those of oncogenesis and tumour progression.


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