Cell cycle represents not only a tightly orchestrated mechanism of cell replication and cell division but it also plays an important role in regulation of cell fate decision. Particularly in the context of pluripotent stem cells or multipotent progenitor cells, regulation of cell fate decision is of paramount importance. It has been shown that human embryonic stem cells (hESCs) show unique cell cycle characteristics, such as short doubling time due to abbreviated G1 phase; these properties change with the onset of differentiation. This review summarizes the current understanding of cell cycle regulation in hESCs. We discuss cell cycle properties as well as regulatory machinery governing cell cycle progression of undifferentiated hESCs. Additionally, we provide evidence that long-term culture of hESCs is accompanied by changes in cell cycle properties as well as configuration of several cell cycle regulatory molecules.
ThomsonJA, Itskovitz-EldorJ, ShapiroSS, WaknitzMA, SwiergielJJ, MarshallVS, JonesJM. Embryonic stem cell lines derived from human blastocysts. Science1998; 282: 1145–7
2.
MaimetsT, NeganovaI, ArmstrongL, LakoM. Activation of p53 by nutlin leads to rapid differentiation of human embryonic stem cells. Oncogene2008; 27: 5277–87
3.
NeganovaI, ZhangX, AtkinsonS, LakoM. Expression and functional analysis of G1 to S regulatory components reveals an important role for CDK2 in cell cycle regulation in human embryonic stem cells. Oncogene2009; 28: 20–30
4.
Van HoofD, MunozJ, BraamSR, PinkseMWH, LindingR, HeckAJR, MummeryCL, KrijgsveldJ. Phosphorylation dynamics during early differentiation of human embryonic stem cells. Cell Stem Cell2009; 5: 214–26
5.
BeckerKA, GhulePN, LianJB, SteinJL, Van WijnenAJ, SteinGS. Cyclin D2 and the CDK substrate p220(NPAT) are required for self-renewal of human embryonic stem cells. J Cell Physiol2010; 222: 456–64
6.
BeckerKA, GhulePN, TherrienJA, LianJB, SteinJL, Van WijnenAJ, SteinGS. Self-renewal of human embryonic stem cells is supported by a shortened G1 cell cycle phase. J Cell Physiol2006; 209: 883–93
7.
BártaT, VinarskyV, HolubcováZ, DolezalováD, VernerJ, PospísilováS, DvorakP, HamplA. Human embryonic stem cells are capable of executing G1/S checkpoint activation. Stem Cells2010; 28: 1143–52
8.
FilipczykAA, LaslettAL, MummeryC, PeraMF. Differentiation is coupled to changes in the cell cycle regulatory apparatus of human embryonic stem cells. Stem Cell Res2007; 1: 45–60
9.
JainAK, AlltonK, IacovinoM, MahenE, MilczarekRJ, ZwakaTP, KybaM, BartonMC. p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells. PLoS Biol2012; 10: e1001268
10.
SelaY, MolotskiN, GolanS, Itskovitz-EldorJ, SoenY. Human embryonic stem cells exhibit increased propensity to differentiate during the G1 phase prior to phosphorylation of retinoblastoma protein. Stem Cells2012; 30: 1097–108
11.
BurdonT, SmithA, SavatierP. Signalling, cell cycle and pluripotency in embryonic stem cells. Trends Cell Biol2002; 12: 432–8
12.
KoledovaZ, KrämerA, KafkovaLR, DivokyV. Cell-cycle regulation in embryonic stem cells: centrosomal decisions on self-renewal. Stem Cells Dev2010; 19: 1663–78
13.
SavatierP, HuangS, SzekelyL, WimanKG, SamarutJ. Contrasting patterns of retinoblastoma protein expression in mouse embryonic stem cells and embryonic fibroblasts. Oncogene1994; 9: 809–18
14.
ZhangX, NeganovaI, PrzyborskiS, YangC, CookeM, AtkinsonSP, AnyfantisG, FenykS, KeithWN, HoareSF, HughesO, StrachanT, StojkovicM, HindsPW, ArmstrongL, LakoM. A role for NANOG in G1 to S transition in human embryonic stem cells through direct binding of CDK6 and CDC25A. J Cell Biol2009; 184: 67–82
15.
EgoziD, ShapiraM, PaorG, Ben-IzhakO, SkoreckiK, HershkoDD. Regulation of the cell cycle inhibitor p27 and its ubiquitin ligase Skp2 in differentiation of human embryonic stem cells. FASEB J2007; 21: 2807–17
16.
SenguptaS, NieJ, WagnerRJ, YangC, StewartR, ThomsonJA. MicroRNA 92b controls the G1/S checkpoint gene p57 in human embryonic stem cells. Stem Cells2009; 27: 1524–8
17.
DolezalovaD, MrazM, BartaT, PlevovaK, VinarskyV, HolubcovaZ, JarosJ, DvorakP, PospisilovaS, HamplA. MicroRNAs regulate p21(Waf1/Cip1) protein expression and the DNA damage response in human embryonic stem cells. Stem Cells2012; 30: 1362–72
18.
FilionTM, QiaoM, GhulePN, MandevilleM, Van WijnenAJ, SteinJL, LianJB, AltieriDC, SteinGS. Survival responses of human embryonic stem cells to DNA damage. J Cell Physiol2009; 220: 586–92
19.
MomcilovićO, ChoiS, VarumS, BakkenistC, SchattenG, NavaraC. Ionizing radiation induces ataxia telangiectasia mutated-dependent checkpoint signaling and G(2) but not G(1) cell cycle arrest in pluripotent human embryonic stem cells. Stem Cells2009; 27: 1822–35
20.
QinH, YuT, QingT, LiuY, ZhaoY, CaiJ, LiJ, SongZ, QuX, ZhouP, WuJ, DingM, DengH. Regulation of apoptosis and differentiation by p53 in human embryonic stem cells. J Biol Chem2007; 282: 5842–52
21.
Anokye-DansoF, SnitowM, MorriseyEE. How microRNAs facilitate reprogramming to pluripotency. J Cell Sci2012; 125: 4179–787
ChoiYJ, LinC-P, HoJJ, HeX, OkadaN, BuP, ZhongY, KimSY, BennettMJ, ChenC, OzturkA, HicksGG, HannonGJ, HeL. miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nat Cell Biol2011; 13: 1353–60
24.
GrecoSJ, LiuK, RameshwarP. Functional similarities among genes regulated by OCT4 in human mesenchymal and embryonic stem cells. Stem Cells2007; 25: 3143–54
DraperJS, MooreHD, RubanLN, GokhalePJ, AndrewsPW. Culture and characterization of human embryonic stem cells. Stem Cells Dev2004; 13: 325–36
27.
EnverT, SonejiS, JoshiC, BrownJ, IborraF, OrntoftT, ThykjaerT, MaltbyE, SmithK, Abu DawudR, JonesM, MatinM, GokhaleP, DraperJ, AndrewsPW. Cellular differentiation hierarchies in normal and culture-adapted human embryonic stem cells. Hum Mol Genet2005; 14: 3129–40
28.
BakerDEC, HarrisonNJ, MaltbyE, SmithK, MooreHD, ShawPJ, HeathPR, HoldenH, AndrewsPW. Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat Biotechnol2007; 25: 207–15
29.
CatalinaP, MontesR, LigeroG, SanchezL, De la CuevaT, BuenoC, LeonePE, MenendezP.Human ESCs predisposition to karyotypic instability: is a matter of culture adaptation or differential vulnerability among hESC lines due to inherent properties?Mol Cancer2008; 7: 76
KunovaM, MatulkaK, EiselleovaL, TrckovaP, HamplA, DvorakP. Development of humanized culture medium with plant-derived serum replacement for human pluripotent stem cells. Reprod Biomed Online2010; 21: 676–86
