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.
Highlights
Embryonic stem cells (ES) are derived from the inner cell mass of the blastocyst and can be cultured indefinitely in vitro while still remaining pluripotent (Evans and Kaufman, 1981; Thomson et al, 1998)
Using imaging techniques based on a Cdk2 sensor, this study showed that the levels of p21 at the Restriction Point 1 in the preceding cell cycle determined whether the cell will proliferate or enter quiescence in the subsequent cycle (Spencer et al, 2013)
Pluripotent stem cells exhibit a highly modified cell cycle which allows for rapid proliferation, keeping pace with the requirement for new cells during embryonic development
Summary
Embryonic stem cells (ES) are derived from the inner cell mass of the blastocyst and can be cultured indefinitely in vitro while still remaining pluripotent (Evans and Kaufman, 1981; Thomson et al, 1998) They can give rise to the three germ layers Endoderm, Mesoderm and Ectoderm in vivo when transplanted into mice or in vitro under appropriate culture conditions. ES cells express a set of genes characteristic of the pluripotent state including transcription factors such as Oct-3/4, Sox, and Nanog (Nichols et al, 1998; Niwa et al, 2000; Avilion et al, 2003; Mitsui et al, 2003; Chambers et al, 2007) These transcription factors are essential in maintaining the pluripotent state and when expressed in other cell types, can confer enhanced stemness. By expressing a combination of four transcription factors that are expressed in ES cells namely, Oct-3/4, Klf, Sox and c-Myc (Yamanaka factors), it is possible to “reprogram” somatic cells to a pluripotent state (Takahashi and Yamanaka, 2006; Takahashi et al, 2007)
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