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Tracking Pluripotent Stem Cells Through the Cell Cycle

Review of “Cell Cycle Dynamics of Human Pluripotent Stem Cells Primed for Differentiation” from STEM CELLS by Stuart P. Atkinson

In previous studies, researchers led by Anshul Kundaje and Sundari Chetty (Stanford University, California, USA) demonstrated how dimethylsulfoxide (DMSO) priming of human pluripotent stem cells (hPSCs) activates the retinoblastoma protein (Rb) and increases the percentage of cells in the G1 phase of the cell cycle, leading to a significant increase in the propensity for differentiation across all germ layers [1, 2].

Now, the team returns with a new STEM CELLS study that employs Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) technology [3] to track cell division in DMSO primed and non-primed hPSCs and describes the overall importance of distinct signaling pathways in the regulation of the developmental potential of hPSCs during early transitory stages [4].

The FUCCI system employs the fusion of different fluorescent proteins to cell cycle ubiquitination oscillators present in G1 (Cdt1-RFP) and S/G2/M phases (Geminin-GFP) and allowed Shcherbina et al. to analyze cells sorted into early G1, late G1, and S/G2/M phases by RNA‐sequencing following adaption of the system to hPSCs. This approach determined that the expression of signaling factors and developmental regulators followed a cell cycle‐specific pattern in primed hPSCs.

Analyses of gene expression alterations following priming highlighted changes to signaling pathways controlling cell proliferation, differentiation, and apoptosis, with the phosphoinositide 3‐kinase (PI3K) pathway playing a significant role. Interestingly, the authors discovered that transiently inhibiting PI3K signaling enhanced the differentiation of hPSC across all germ layers, suggesting a significant role for this pathway in the early transitory states of hPSCs toward differentiation. Of note, priming for differentiation did not affect the expression of pluripotency-associated genes through the cell cycle.

The authors note that their findings agree with previous studies stating that PI3K‐dependent signals promote embryonic stem cell proliferation and support the importance of distinct cell cycle phases in the orchestration of cell fate [5, 6]. Furthermore, they anticipate that targeting the pathways uncovered in their study may aid the differentiation of hPSCs towards specific fates and improve their applicability to regenerative approaches. 

For more on tracking pluripotent stem cells through the cell cycle, stay tuned to the Stem Cells Portal.

References

  1. Chetty S, Pagliuca FW, Honore C, et al., A simple tool to improve pluripotent stem cell differentiation. Nature Methods 2013;10:553.
  2. Li J, Narayanan C, Bian J, et al., A transient DMSO treatment increases the differentiation potential of human pluripotent stem cells through the Rb family. PLOS ONE 2018;13:e0208110.
  3. Sakaue-Sawano A, Kurokawa H, Morimura T, et al., Visualizing Spatiotemporal Dynamics of Multicellular Cell-Cycle Progression. Cell 2008;132:487-498.
  4. Shcherbina A, Li J, Narayanan C, et al., Brief Report: Cell Cycle Dynamics of Human Pluripotent Stem Cells Primed for Differentiation. STEM CELLS 2019;37:1151-1157.
  5. Burdon T, Smith A, and Savatier P, Signalling, cell cycle and pluripotency in embryonic stem cells. Trends in Cell Biology 2002;12:432-438.
  6. Gonzales Kevin Andrew U, Liang H, Lim Y-S, et al., Deterministic Restriction on Pluripotent State Dissolution by Cell-Cycle Pathways. Cell 2015;162:564-579.