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Human Molecular Genetics Advance Access originally published online on September 13, 2005
Human Molecular Genetics 2005 14(21):3129-3140; doi:10.1093/hmg/ddi345
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© The Author 2005. Published by Oxford University Press. All rights reserved.
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Cellular differentiation hierarchies in normal and culture-adapted human embryonic stem cells

Tariq Enver1, Shamit Soneji1, Chirag Joshi1, John Brown1, Francisco Iborra1, Torben Orntoft2, Thomas Thykjaer2, Edna Maltby3, Kath Smith3, Raed Abu Dawud4, Mark Jones4, Maryam Matin5, Paul Gokhale4, Jonathan Draper4 and Peter W. Andrews4,*

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

* To whom correspondence should be addressed. Tel: +44 1142224173; Fax: +44 1142222399; Email: p.w.andrews{at}sheffield.ac.uk

Received May 26, 2005; Revised August 1, 2005; Accepted September 7, 2005

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 and 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 programmes 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. On the basis of 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. As 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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