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First published online 10 January 2007
doi: 10.1242/dev.02787

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How is pluripotency determined and maintained?

Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology (CDB), 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 6500047, Japan. Laboratory for Development and Regenerative Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho, Chuo-ku, Kobe, Hyogo 6500017, Japan.

View larger version (21K): [in this window] [in a new window]   Fig. 1. Pluripotent lineages in the mouse embryo. A schematic view of mouse preimplantation development. (A) Pluripotent stem cells (green) are imaged in a morula as the inner cells, which (B) then form the inner cell mass (ICM) of the blastocyst. (C) After giving rise to the primitive endoderm on the surface of the ICM, pluripotent stem cells then form the epiblast and start to proliferate rapidly after implantation. (D) They then form the primitive ectoderm, a monolayer epithelium that has restricted pluripotency which goes on to give rise to the germ cell lineage and to the somatic lineages of the embryo. Certain key transcription factors (blue) are required for the differentiation of the various embryonic lineages.

View larger version (50K): [in this window] [in a new window]   Fig. 2. Differentiation of mouse ES cells. (A) Mouse ES cells differentiate into three cell types - primitive endoderm, trophectoderm (TE) and primitive ectoderm - mimicking the differentiation potential of pluripotent stem cells in preimplantation embryos. (B-E) Different culture conditions can induce ES cells to differentiate into certain lineages. (B) In the absence of Lif and in the presence of an excess of Oct3/4, ES cells differentiate into primitive endoderm-like cells, whereas (C) in the absence of Nanog and in the presence of Gata6, they differentiate into parietal endoderm-like cells. (D,E) Removing Oct3/4 from, and adding Cdx2 to, ES cell culture induces TE-like differentiation. MEFc, mouse embryonic fibroblast conditioned medium.

View larger version (18K): [in this window] [in a new window]   Fig. 3. Regulation of proliferation of mouse ES cells. (A) Pluripotent transcription factors activate the expression of (B) certain effectors that drive ES cell proliferation. Among these, Eras and Tcl1 stimulate the (C) phosphoinositide-3-kinase (PI3K)/Akt signaling pathway to promote the cell cycle, whereas b-Myb and c-Myc activate the progression of the cell cycle directly. How Utf1 and Sall4 affect ES cell proliferation remains unknown.

View larger version (22K): [in this window] [in a new window]   Fig. 4. A transcription factor network to control ES cell self-renewal and differentiation. (A) Transcriptional regulation of the mouse Oct3/4 gene. There are four evolutionally conserved regions (CR1-4) that contain multiple transcription factor (TF) binding sites. The TFs that bind to these sites are shown above and either activate (red) or repress (blue) transcription. DE, distal enhancer; PE, proximal enhancer; PP, proximal promoter. (B) Transcription factor networks for pluripotent stem cells (green), trophectoderm (yellow) and primitive (extraembryonic) endoderm (blue). Positive-feedback loops between Oct3/4, Sox2 and Nanog maintain their expression to promote continuous ES cell self-renewal. Cdx2 is autoregulated and forms a reciprocal inhibitory loop with Oct3/4, which acts to establish their mutually exclusive expression patterns. A similar regulatory loop, not yet confirmed, might exist for Nanog and Gata6. A combination of positive-feedback loops and reciprocal inhibitory loops converts continuous input parameters into a bimodal probability distribution, resulting in a clear segregation of these cell lineages (see text for details). Coup-tfs and Gcnf act as a negative-feedback system to repress Oct3/4 completely.

View larger version (40K): [in this window] [in a new window]   Fig. 5. Characteristics of the pluripotent epigenome. (A) Nuclei of undifferentiated (left) and differentiated (right) ES cells. The nucleus shrinks and the distribution of electrondense areas, mainly heterochromatin, changes dramatically when ES cells are induced to differentiate into primitive endoderm by the ectopic expression of Gata6. (Electron micrographs courtesy of Naoko Ikue and Shigenobu Yonehara.) (B) Epigenetic features of the pluripotent cell nucleus. The volume of the nucleus is larger than that of a differentiated cell as a result of the relaxed chromatin structure. Small regions of perinuclear heterochromatin exist, but most of the chromatin exists as euchromatin, bearing histone marks associated with transcriptional activity. The hyperdynamics of chromatin proteins (green) might contribute to the maintenance of euchromatin. Bivalent domains are also a feature of the pluripotent epigenome, in which active histone marks (such as H3K4me) are flanked by transcriptionally repressive histone marks (such as H3K9me).

View larger version (13K): [in this window] [in a new window]   Fig. 6. Establishment of pluripotency in somatic cell nuclei. In a recent study (Takahashi and Yamanaka, 2006), four transcription factors, Oct3/4, Sox2, Klf4 and c-Myc, were found to be sufficient to establish pluripotency in the nuclei of fibroblasts. Oct3/4, Sox2 and Klf4 might function together to activate target genes to establish the stable pluripotent transcription factor network, as well as the pluripotent epigenome, whereas c-Myc might enhance the accessibility of target genes by stimulating DNA replication.