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

Abstract

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.proliferation control | differentiation modeling | guided differentiation | systems biology

A Src inhibitor regulates the cell cycle of human pluripotent stem cells and improves directed differentiation

“…Consistent with prior reports, treatment of hPSCs with other inhibitors to perturb various cell cycle-related kinase signaling pathways had a minimal or moderate effect on improving differentiation potential (Smith, 2001;Orford and Scadden, 2008;Li and Kirschner, 2014). Treatment with a Cdk2 inhibitor at 5-10 µM induced ∼20% of the cells to differentiate into Brachy+ cells but was associated with a substantial degree of cell loss at higher doses (Fig.…”

Multiple cell and population-level interactions with mouse embryonic stem cell heterogeneity

“…Correlations between reporter expression and cycle duration also occurred following treatment with 2i (supplementary material Table S1). In previous experiments in mESCs, artificial extension of G1 did not alter Nanog levels (Li et al, 2012) and serum level modulation showed a similar resistance of Nanog and Oct4 (Pou5f1) to loss of growth potential (Li and Kirschner, 2014). Together, these data suggest that the extended cell cycle effects we observed are a feature rather than a driver of enhanced pluripotency.…”

“…Slow-cycling stem cell states were previously inferred in cancer biology, although differences in cycle times (Sharma et al, 2010) are more extreme. Previous studies did not observe changes in Nanog expression caused by disruption of growth potential or G1 (Li et al, 2012;Li and Kirschner, 2014). Together, these data indicate that longer cell cycles are a feature, rather than a cause, of the pluripotent state.…”

“…Is ESC cell cycle behaviour a determinant of gene expression? In mESCs, treatments prolonging cell cycles do not perceptibly alter the expression of pluripotency genes such as Nanog (Li et al, 2012;Li and Kirschner, 2014). However, although early embryonic cell cycles can be highly synchronous, many eukaryotic cycles are highly heterogeneous (Brooks, 1981;Di Talia et al, 2007;Muramoto and Chubb, 2008) and, with different signalling associated with different cycle stages, cycle variability potentially provides a driver of gene expression heterogeneity.…”

A systems biology approach identifies a gene regulatory network in parotid acinar cell differentiation.

“…It has often been observed that exiting the cell cycle will stimulate terminal differentiation, while activating the cell cycle is an inhibitor of differentiation [130]. Known direct targets of the let-7 family include Igf2bp2, an mRNA binding protein which is known to enhance the translation of many genes including several oncogenes and activators of proliferation, Igf2, and c-myc [131].…”