Editors' ChoiceStem Cells

Cycling to Live Differently

Science Signaling  01 Oct 2013:
Vol. 6, Issue 295, pp. ec235
DOI: 10.1126/scisignal.2004767

Human embryonic stem cells (hESCs) provide a model for understanding the factors that mediate cell fate determination during human development and are a potential resource for cell replacement therapies. Molecular signals usually promote cells to differentiate during the G1 phase of the cell cycle, and the phase of the cell cycle can influence developmental signal transduction. Pauklin and Vallier discovered that the phase of the cell cycle determined which lineage hESCs can become. Using a fluorescent reporter to sort hESCs according to the phase of the cell cycle and then testing the potential of those populations to become each of the three germ layers by growing cells in three different germ layer induction media, they found that early G1 hESCs had an increased potential to become endoderm and mesoderm, whereas those in late G1 had increased neuroectodermal potential. The hESCs in S or G2/M phase had little potential for differentiation into any germ layer. Activin and Nodal signaling through Smads 2 and 3 (Smad2/3) are the primary factors that induce endodermal differentiation. After a brief exposure to Activin A, activation of a Smad2/3 reporter and binding of Smad2/3 to the promoter of endodermal specification genes were greatest during early G1 of sorted hESCs. Cyclins D1, D2, and D3 (cycDs) promote progression through G1. Simultaneous knockdown of all three cycDs enhanced Smad2/3 nuclear localization and reporter activation and the endodermal potential of early G1 hESCs, whereas overexpression of all three had the opposite effect. Pharmacological inhibition of the cycD-dependent kinases CDK4 and CDK6 decreased phosphorylation of the linker region of Smad2/3 that inhibits nuclear translocation and is associated with late G1 and promoted Smad2/3 association with chromatin in late G1 hESCs, and substituted for Activin in endodermal induction medium. Thus, these findings provide a molecular mechanism to explain how hESCs can coordinate the cell cycle with cell fate decisions and provide new approaches for directed differentiation (see Dalton).

S. Pauklin, L. Vallier, The cell-cycle state of stem cells determines cell fate propensity. Cell 155, 135–147 (2013). [PubMed]

S. Dalton, G1 compartmentalization and cell fate coordination. Cell 155, 13–14 (2013). [PubMed]