Molecular ties between the cell cycle and differentiation in embryonic stem cells

Significance The role of the cell cycle as an inhibitor of the late stages of cellular differentiation is well known, but in early embryonic development its role is mysterious. Normally, embryonic stem (ES) cells proliferate quickly during differentiation and do not differentiate simply by cell cycle slowing. In this paper, it is shown that the role of the cell cycle in terminal stages of differentiation can be adapted for and extended into ES cells. Methods aimed at inhibiting the cell cycle drive a rapid, condensed differentiation to terminally differentiated cells, demonstrating that the cell cycle is a principle rate-limiting step of differentiation throughout early and late stages. This is beneficial as well for accelerating differentiation in ES cell applications. Attainment of the differentiated state during the final stages of somatic cell differentiation is closely tied to cell cycle progression. Much less is known about the role of the cell cycle at very early stages of embryonic development. Here, we show that molecular pathways involving the cell cycle can be engineered to strongly affect embryonic stem cell differentiation at early stages in vitro. Strategies based on perturbing these pathways can shorten the rate and simplify the lineage path of ES differentiation. These results make it likely that pathways involving cell proliferation intersect at various points with pathways that regulate cell lineages in embryos and demonstrate that this knowledge can be used profitably to guide the path and effectiveness of cell differentiation of pluripotent cells.