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      Capturing Pluripotency

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      1 , 1 ,
      Cell
      Cell Press

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          Abstract

          In this Essay, we argue that pluripotent epiblast founder cells in the embryo and embryonic stem (ES) cells in culture represent the ground state for a mammalian cell, signified by freedom from developmental specification or epigenetic restriction and capacity for autonomous self-replication. We speculate that cell-to-cell variation may be integral to the ES cell condition, safe-guarding self-renewal while continually presenting opportunities for lineage specification.

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          Most cited references24

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          Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells.

          Embryonic stem (ES) cells undergo extended proliferation while remaining poised for multilineage differentiation. A unique network of transcription factors may characterize self-renewal and simultaneously suppress differentiation. We applied expression cloning in mouse ES cells to isolate a self-renewal determinant. Nanog is a divergent homeodomain protein that directs propagation of undifferentiated ES cells. Nanog mRNA is present in pluripotent mouse and human cell lines, and absent from differentiated cells. In preimplantation embryos, Nanog is restricted to founder cells from which ES cells can be derived. Endogenous Nanog acts in parallel with cytokine stimulation of Stat3 to drive ES cell self-renewal. Elevated Nanog expression from transgene constructs is sufficient for clonal expansion of ES cells, bypassing Stat3 and maintaining Oct4 levels. Cytokine dependence, multilineage differentiation, and embryo colonization capacity are fully restored upon transgene excision. These findings establish a central role for Nanog in the transcription factor hierarchy that defines ES cell identity.
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            BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3.

            The cytokine leukemia inhibitory factor (LIF) drives self-renewal of mouse embryonic stem (ES) cells by activating the transcription factor STAT3. In serum-free cultures, however, LIF is insufficient to block neural differentiation and maintain pluripotency. Here, we report that bone morphogenetic proteins (BMPs) act in combination with LIF to sustain self-renewal and preserve multilineage differentiation, chimera colonization, and germline transmission properties. ES cells can be propagated from single cells and derived de novo without serum or feeders using LIF plus BMP. The critical contribution of BMP is to induce expression of Id genes via the Smad pathway. Forced expression of Id liberates ES cells from BMP or serum dependence and allows self-renewal in LIF alone. Upon LIF withdrawal, Id-expressing ES cells differentiate but do not give rise to neural lineages. We conclude that blockade of lineage-specific transcription factors by Id proteins enables the self-renewal response to LIF/STAT3.
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              Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway.

              It has been thought that early inner cell mass (ICM) is a homogeneous population and that cell position in the ICM leads to the formation of two lineages, epiblast (EPI) and primitive endoderm (PE), by E4.5. Here, however, we show that the ICM at E3.5 is already heterogeneous. The EPI- and PE-specific transcription factors, Nanog and Gata6, were expressed in the ICM in a random "salt and pepper" pattern, as early as E3.5, in a mutually exclusive manner. Lineage tracing showed predominant lineage restriction of single ICM cells at E3.5 to either lineage. In embryos lacking Grb2 where no PE forms, Gata6 expression was lost and all ICM cells were Nanog positive. We propose a model in which the ICM develops as a mosaic of EPI and PE progenitors at E3.5, dependent on Grb2-Ras-MAP kinase signaling, followed by later segregation of the progenitors into the appropriate cell layers.
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                Author and article information

                Journal
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                22 February 2008
                22 February 2008
                : 132
                : 4
                : 532-536
                Affiliations
                [1 ]Wellcome Trust Centre for Stem Cell Research and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QR, UK
                Author notes
                []Corresponding author ags39@ 123456cscr.cam.ac.uk
                Article
                CELL3784
                10.1016/j.cell.2008.02.006
                2427053
                18295569
                e5cf1163-042a-4973-8cbf-0ea3291b5878
                © 2008 ELL & Excerpta Medica.

                This document may be redistributed and reused, subject to certain conditions.

                History
                Categories
                Essay

                Cell biology
                Cell biology

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