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Review
. 2018 Jun 19;6:57.
doi: 10.3389/fcell.2018.00057. eCollection 2018.

Cycling to Meet Fate: Connecting Pluripotency to the Cell Cycle

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Free PMC article
Review

Cycling to Meet Fate: Connecting Pluripotency to the Cell Cycle

Lamuk Zaveri et al. Front Cell Dev Biol. .
Free PMC article

Abstract

Pluripotent stem cells are characterized by their high proliferative rates, their ability to self-renew and their potential to differentiate to all the three germ layers. This rapid proliferation is brought about by a highly modified cell cycle that allows the cells to quickly shuttle from DNA synthesis to cell division, by reducing the time spent in the intervening gap phases. Many key regulators that define the somatic cell cycle are either absent or exhibit altered behavior, allowing the pluripotent cell to bypass cell cycle checkpoints typical of somatic cells. Experimental analysis of this modified stem cell cycle has been challenging due to the strong link between rapid proliferation and pluripotency, since perturbations to the cell cycle or pluripotency factors result in differentiation. Despite these hurdles, our understanding of this unique cell cycle has greatly improved over the past decade, in part because of the availability of new technologies that permit the analysis of single cells in heterogeneous populations. This review aims to highlight some of the recent discoveries in this area with a special emphasis on different states of pluripotency. We also discuss the highly interlinked network that connects pluripotency factors and key cell cycle genes and review evidence for how this interdependency may promote the rapid cell cycle. This issue gains translational importance since disruptions in stem cell proliferation and differentiation can impact disorders at opposite ends of a spectrum, from cancer to degenerative disease.

Keywords: cell cycle; embryonic stem cells; induced pluripotent stem cells; pluripotency; reprogramming.

Figures

Figure 1
Figure 1
Cell cycles vary between somatic and pluripotent stem cells. Embryonic stem cells exhibit faster proliferation rates, which is reflected in their modified cell cycles. In comparison to the somatic cell cycle in embryonic fibroblasts with a cell cycle duration of ~20 h (B) hESC display a cell cycle duration of 15 h (A) while in mES, it is shortened to ~10 h (C). The main difference between the three cell cycles is the length of the G1 phase which is highly reduced in mES, with hESC exhibiting a shortened G1 and somatic cells exhibiting a relatively longer G1. The weighted arrows indicate Cyclin-Cdk complex activity, which in somatic cells and hESC exhibit a canonical oscillatory behavior across the cell cycle. In mES, Cyclin B/Cdk1 is the only complex that displays this oscillatory behavior, while Cyclin E/Cdk2, Cyclin A/Cdk2 are active throughout the mES cell cycle and Cyclin D/Cdk4/Cdk6 exhibits very low activity during the reduced G1. RB, the pivotal regulator of the Restriction point in G1 is active (RB) at the start of G1 and gets progressively phosphorylated across G1 leading to its inactivation (RBppp), and allows the cell to cross the G1/S checkpoint. mES have a perpetually inactive RBppp, thereby allowing unfettered transit through G1.
Figure 2
Figure 2
Pluripotency factor Oct-3/4 integrates stemness with cell cycle in cell cycle speed. Oct-3/4 plays an important role in maintaining the different phases of the cell cycle in ES cells. Oct-3/4 in collaboration with Sox-2, regulates Cyclin D/Cdk activity via miR-302, ensuring a shorter G1. Oct-3/4 represses p21 activity by directly inhibiting its expression and indirectly, by inhibiting p53, a potent activator of p21 expression. Oct-3/4 positively regulates expression of E2F3a which is the main E2F activator for Cyclin A and Cdk1 expression. Oct-3/4 positively regulates Cyclin F which aids in the migration of Cyclin B into the cell nucleus, thereby promoting G2/M. The arrows indicate positive regulation, the T-line represents inhibition.

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