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Review
.2013 Apr 15;451(2):135-43.
doi: 10.1042/BJ20121627.

The cell cycle and pluripotency

Affiliations
Review

The cell cycle and pluripotency

Christopher Hindley et al. Biochem J..

Abstract

PSCs (pluripotent stem cells) possess two key properties that have made them the focus of global research efforts in regenerative medicine: they have unlimited expansion potential under conditions which favour their preservation as PSCs and they have the ability to generate all somatic cell types upon differentiation (pluripotency). Conditions have been defined in vitro in which pluripotency is maintained, or else differentiation is favoured and is directed towards specific somatic cell types. However, an unanswered question is whether or not the core cell cycle machinery directly regulates the pluripotency and differentiation properties of PSCs. If so, then manipulation of the cell cycle may represent an additional tool by which in vitro maintenance or differentiation of PSCs may be controlled in regenerative medicine. The present review aims to summarize our current understanding of links between the core cell cycle machinery and the maintenance of pluripotency in ESCs (embryonic stem cells) and iPSCs (induced PSCs).

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Figures

Figure 1
Figure 1. Schematic diagram comparing the cell cycle in somatic (MEF) and pluripotent cells
For each panel, the first part is a graphical representation of the number of cells in each phaseof the cell cycle within a population, as assessed by propidium iodide staining and flow cytometricanalysis. Peaks represent 2N and 4N DNA content. The second part of each panel is a summary for anindividual cell of the relative amounts of time spent in each cell cycle phase. In addition theaverage total time taken to complete one cycle is presented for each cell type. It is clear that,proportionally, pluripotent cells have a shortened G1- and a longer S-phase for eachcycle than somatic cells, although absolute S-phase length is comparable.
Figure 2
Figure 2. Schematic diagram of how S-phase may maintain the euchromatic state in PSCs
A short G1/S-phase ratio results in more frequent passage of the replication fork, andalthough histone octamers and their modifications are conserved, linker histone H1 binding to DNA isnot (left-hand side). This inhibits the formation of higher-order chromatin structure, which is thenpermissive once the G1/S-phase ratio increases (right-hand side).
Figure 3
Figure 3. Potential interactions between the cell cycle and the pluripotency transcription network in pluripotent cells and during reprogramming
(A) A master regulator, such as Myc, regulates both the pluripotency network and thecell cycle, which co-operate to down-regulate the somatic transcription network. (B)The pluripotent cell cycle structure stabilizes the pluripotent transcription network anddestabilizes the somatic cell transcription network directly. (C) The pluripotencytranscription network and the cell cycle act in a positive-feedback loop that represses the somaticcell transcription network.
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References

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    1. Sherr C. J., Roberts J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13:1501–1512. - PubMed
    1. Stead E., White J., Faast R., Conn S., Goldstone S., Rathjen J., Dhingra U., Rathjen P., Walker D., Dalton S. Pluripotent cell division cycles are driven by ectopic Cdk2, cyclin A/E and E2F activities. Oncogene. 2002;21:8320–8333. - PubMed
    1. Lawson K. A., Meneses J. J., Pedersen R. A. Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. Development. 1991;113:891–911. - PubMed
    1. Singh A. M., Dalton S. The cell cycle and Myc intersect with mechanisms that regulate pluripotency and reprogramming. Cell Stem Cell. 2009;5:141–149. - PMC - PubMed

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