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DNA Research Advance Access published online on December 26, 2008
DNA Research, doi:10.1093/dnares/dsn035
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Published by Oxford University Press 2008
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@oxfordjournals.org

Defining Developmental Potency and Cell Lineage Trajectories by Expression Profiling of Differentiating Mouse Embryonic Stem Cells

Kazuhiro Aiba1 {dagger} {ddagger}, Timur Nedorezov1 {dagger}, Yulan Piao1, Akira Nishiyama1, Ryo Matoba1 §, Lioudmila V. Sharova1, Alexei A. Sharov1, Shinya Yamanaka2, Hitoshi Niwa3 and Minoru S. H. Ko1,*

1 Developmental Genomics and Aging Section, Laboratory of Genetics, National Institute on Aging, NIH, Baltimore, MD 21224, USA
2 Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Kyoto 332-0012, Japan
3 Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan

Received 1 December 2008 ; accepted 11 December 2008.

Biologists rely on morphology, function and specific markers to define the differentiation status of cells. Transcript profiling has expanded the repertoire of these markers by providing the snapshot of cellular status that reflects the activity of all genes. However, such data have been used only to assess relative similarities and differences of these cells. Here we show that principal component analysis of global gene expression profiles map cells in multidimensional transcript profile space and the positions of differentiating cells progress in a stepwise manner along trajectories starting from undifferentiated embryonic stem (ES) cells located in the apex. We present three ‘cell lineage trajectories’, which represent the differentiation of ES cells into the first three lineages in mammalian development: primitive endoderm, trophoblast and primitive ectoderm/neural ectoderm. The positions of the cells along these trajectories seem to reflect the developmental potency of cells and can be used as a scale for the potential of cells. Indeed, we show that embryonic germ cells and induced pluripotent cells are mapped near the origin of the trajectories, whereas mouse embryo fibroblast and fibroblast cell lines are mapped near the far end of the trajectories. We suggest that this method can be used as the non-operational semi-quantitative definition of cell differentiation status and developmental potency. Furthermore, the global expression profiles of cell lineages provide a framework for the future study of in vitro and in vivo cell differentiation.

Key words: embryonic stem; embryonic germ; induced pluripotent stem; mouse embryo fibroblast; embryonal carcinoma; retinoic acids; neural stem/progenitor; trophoblast stem; principal component analysis; leukemia inhibitory factor; epigenetic landscape; Waddington; developmental potency; cell lineage trajectory; gene expression profiling; DNA microarray analysis

* To whom correspondence should be addressed. Tel. +1 410-558-8359. Fax. +1 410-558-8331. E-mail: kom{at}mail.nih.gov

{dagger} These authors contributed equally to this work.

{ddagger} Present address: Stem Cell and Drug Discovery Institute, Kyoto Research Park, Kyoto, Kyoto 600-8813, Japan.

§ Present address: DNA Chip Research Inc., Yokohama, Kanagawa 230-0045, Japan.


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