Pluripotency Factors in Embryonic Stem Cells Regulate Differentiation into Germ Layers

FAS Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA.
Cell (Impact Factor: 32.24). 06/2011; 145(6):875-89. DOI: 10.1016/j.cell.2011.05.017
Source: PubMed

ABSTRACT Cell fate decisions are fundamental for development, but we do not know how transcriptional networks reorganize during the transition from a pluripotent to a differentiated cell state. Here, we asked how mouse embryonic stem cells (ESCs) leave the pluripotent state and choose between germ layer fates. By analyzing the dynamics of the transcriptional circuit that maintains pluripotency, we found that Oct4 and Sox2, proteins that maintain ESC identity, also orchestrate germ layer fate selection. Oct4 suppresses neural ectodermal differentiation and promotes mesendodermal differentiation; Sox2 inhibits mesendodermal differentiation and promotes neural ectodermal differentiation. Differentiation signals continuously and asymmetrically modulate Oct4 and Sox2 protein levels, altering their binding pattern in the genome, and leading to cell fate choice. The same factors that maintain pluripotency thus also integrate external signals and control lineage selection. Our study provides a framework for understanding how complex transcription factor networks control cell fate decisions in progenitor cells.

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    • "This simple and elegant model, however, does not adequately explain the mechanisms describing the exit from pluripotency, and moreover, a number of recent studies challenge this classical view. First, several studies show that pluripotency factors may have a direct role in promoting differentiation to different cell lineages [2] [3] [4]. These studies raise the possibility that the so-called " pluripotency factors " have a role not only in maintaining self-renewal, but also in driving lineage specification to exit the pluripotent state. "
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    ABSTRACT: Cellular heterogeneity is now considered an inherent property of most stem cell types, including pluripotent stem cells, somatic stem cells, and cancer stem cells, and this heterogeneity can exist at the epigenetic, transcriptional, and posttranscriptional levels. Several studies have indicated that the stochastic activation of signaling networks may promote heterogeneity and further that this heterogeneity may be reduced by their inhibition. But why different cells in the same culture respond in a nonuniform manner to the identical exogenous signals has remained unclear. Recent studies now demonstrate that the cell cycle position directly influences lineage specification and specifically that pluripotent stem cells initiate their differentiation from the G1 phase. These studies suggest that cells in G1 are uniquely “poised” to undergo cell specification. G1 cells are therefore more prone to respond to differentiation cues, which may explain the heterogeneity of developmental factors, such as Gata6, and pluripotency factors, such as Nanog, in stem cell cultures. Overall, this raises the possibility that G1 serves as a “Differentiation Induction Point.” In this review, we will reexamine the literature describing heterogeneity of pluripotent stem cells, while highlighting the role of the cell cycle as a major determinant.
    Stem cell International 05/2015; 2015:1-9. DOI:10.1155/2015/219514 · 2.81 Impact Factor
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    • "RT-PCR assays also demonstrated that NOGGIN and SB431542 decreased OCT4 and increased PAX6 mRNA levels. In contrast, weak or no mRNA expression of BRACHYURY and GATA2, two non-NE markers [3] [18], was detected despite the presence of NOGGIN and SB431542 (Fig. 3G). "
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    ABSTRACT: Directed neural differentiation of human embryonic stem cells (ESCs) enables researchers to generate diverse neuronal populations for human neural development study and cell replacement therapy. To realize this potential, it is critical to precisely understand the role of various endogenous and exogenous factors involved in neural differentiation. Cell density, one of the endogenous factors, is involved in the differentiation of human ESCs. Seeding cell density can result in variable terminal cell densities or localized cell densities (LCDs), giving rise to various outcomes of differentiation. Thus, understanding how LCD determines the differentiation potential of human ESCs is important. The aim of this study is to highlight the role of LCD in the differentiation of H9 human ESCs into neuroectoderm (NE), the primordium of the nervous system. We found the initially seeded cells form derived cells with variable LCDs and subsequently affect the NE differentiation. Using a newly established method for the quantitative examination of LCD, we demonstrated that in the presence of induction medium supplemented with or without SMAD signaling blockers, high LCD promotes the differentiation of NE. Moreover, SMAD signaling blockade promotes the differentiation of NE but not non-NE germ layers, which is dependent on high LCDs. Taken together, this study highlights the need to develop innovative strategies or techniques based on LCDs for generating neural progenies from human ESCs.
    Biochemical and Biophysical Research Communications 10/2014; 452(4):895-900. DOI:10.1016/j.bbrc.2014.08.137 · 2.30 Impact Factor
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    • "Both Oct4 and Sox2 are expressed continually and relatively uniformly in ESCs under all standard conditions. In the acute absence of Oct4 or Sox2, ESCs progressively differentiate toward trophectoderm derivatives , while overexpression also elicits lineage specification, implying that precisely regulated OCT4 and SOX2 levels are crucial for the balance between self-renewal and differentiation (Masui et al., 2007; Niwa et al., 2000; Thomson et al., 2011). "
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    ABSTRACT: Pluripotency is the remarkable capacity of a single cell to engender all the specialized cell types of an adult organism. This property can be captured indefinitely through derivation of self-renewing embryonic stem cells (ESCs), which represent an invaluable platform to investigate cell fate decisions and disease. Recent advances have revealed that manipulation of distinct signaling cues can render ESCs in a uniform "ground state" of pluripotency, which more closely recapitulates the pluripotent naive epiblast. Here we discuss the extrinsic and intrinsic regulatory principles that underpin the nature of pluripotency and consider the emerging spectrum of pluripotent states.
    Cell Stem Cell 10/2014; 15(4):416-430. DOI:10.1016/j.stem.2014.09.015 · 22.27 Impact Factor
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