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ESCs Need a Pause for Lineage-Specific Differentiation

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Review of “Lineage-Specific Early Differentiation of Human Embryonic Stem Cells Requires a G2 Cell Cycle Pause” from Stem Cells by Stuart P. Atkinson

Throughout the daily cycle of our lives, many of us often pause to think; who am I and where am I going? Well, it turns out that we are not alone! Pluripotent human embryonic stem cells (ESCs) are locked into their own special (cell) cycle [1, 2], characterized by a shortened phase of the cycle known as G1 [3]. Interestingly, new research from the laboratory of Gary S. Stein (University of Vermont College of Medicine, USA) has shown that the hESC cell cycle also requires a “pause” of its own in order for lineage-specific differentiation to occur [4]. This new study, published in Stem Cells, highlights an essential role for the WEE1 kinase and hopes to provide new insights into the early events of lineage-specific hESC commitment.

The authors first confirmed that during early lineage commitment (days 1 – 3), the doubling time of ESCs increases from around 17 hours to 47 hours, and then reduces to around 27 hours (3 – 5 days). The increased doubling time at these early stages correlated to the accumulation of cells in the S/G2 and the G2/M phases, so providing evidence for a G2 cell cycle pause during early differentiation.

To discover the genes involved in this process, the study examined global gene expression during early differentiation. The WEE1 kinase, which phosphorylates and inhibits CDK1 [5], was highly expressed during the cell cycle pause, and therefore may be the major factor leading to the inhibited progress into mitosis and the cell cycle pause. However, the study also highlighted that this mechanism is lineage-specific; ectodermal differentiation did not lead to cell cycle stage-specific accumulation or WEE1 up-regulation while mesodermal and endodermal differentiation did.

We can conclude, for human ESCs anyway, that length does indeed matter! A shortened G1 phase boosts proliferation, and we now know that lineage-specific differentiation requires a lengthened G2 phase caused by a G2 pause. The authors suggest that the pause “may function as a transition point between active maintenance of pluripotency and the incorporation of differentiation cues before commitment to lineage determination”. Hopefully, further research will delineate the exact mechanisms controlling this transition point, and reveal more about the pluripotent state and lineage-specific differentiation. For now, see the adjoined figure summarizing current thinking!

References

  1. Kapinas K, Grandy R, Ghule P, et al. The abbreviated pluripotent cell cycle. J Cell Physiol 2013;228:9-20.
  2. White J and Dalton S Cell cycle control of embryonic stem cells. Stem Cell Reviews 2005;1:131-138.
  3. Becker KA, Ghule PN, Therrien JA, et al. Self-renewal of human embryonic stem cells is supported by a shortened G1 cell cycle phase. J Cell Physiol 2006;209:883-893.
  4. Van Oudenhove JJ, Grandy RA, Ghule PN, et al. Lineage-Specific Early Differentiation of Human Embryonic Stem Cells Requires a G2 Cell Cycle Pause. Stem Cells 2016;34:1765-1775.
  5. McGowan CH and Russell P Human Wee1 kinase inhibits cell division by phosphorylating p34cdc2 exclusively on Tyr15. EMBO J 1993;12:75-85.