Abstract
ABSTRACTEmbryonic Stem cells derived from the epiblast tissue of the mammalian blastocyst retain the capability to differentiate into any adult cell type and are able to self-renew indefinitely under appropriate culture conditions. Despite the large amount of knowledge that we have accumulated to date about the regulation and control of self-renewal, efficient directed differentiation into specific tissues remains elusive. In this work, we have analysed in a systematic manner the interaction between the dynamics of loss of pluripotency and Activin/Nodal, BMP4 and Wnt signalling in fate assignment during the early stages of differentiation of mouse ES cells in culture. During the initial period of differentiation, cells exit from pluripotency and enter an Epi-like state. Following this transient stage, and under the influence of Activin/Nodal and BMP signalling, cells face a fate choice between differentiating into neuroectoderm and contributing to Primitive Streak fates. We find that Wnt signalling does not suppress neural development as previously thought and that it aids both fates in a context dependent manner. Our results suggest that as cells exit pluripotency they are endowed with a primary neuroectodermal fate and that the potency to become endomesodermal rises with time. We suggest that this situation translates into a “race for fates” in which the neuroectodermal fate has an advantage.
Highlights
Embryonic Stem (ES) cells are clonal populations derived from early mammalian blastocysts that have the ability to self renew as well as the capacity to differentiate into all embryonic cell types of an organism in culture and contribute to the normal development of an embryo into an organism, i.e. they are pluripotent (Bradley et al, 1984; Smith, 2001; Nichols and Smith, 2011)
We have analysed the role of signalling in fate assignment during the early stages of differentiation of mouse ES cell populations in culture
While there are many studies of ES cell differentiation into particular cell types, there is no integrated analysis of the kind that we have performed here
Summary
Embryonic Stem (ES) cells are clonal populations derived from early mammalian blastocysts that have the ability to self renew as well as the capacity to differentiate into all embryonic cell types of an organism in culture and contribute to the normal development of an embryo into an organism, i.e. they are pluripotent (Bradley et al, 1984; Smith, 2001; Nichols and Smith, 2011). Controlled application of defined cocktails of signalling. Despite notable successes, these protocols remain tinkering exercises performed with limited understanding of the routes and mechanisms that control differentiation. Perhaps for this reason, questions remain as to the similarities and differences between the events in ES cells and in the embryo (Gadue et al, 2006; Chen et al, 2013). Gaining insights into the mechanisms of differentiation in culture will have an impact in our ability to harness the potential of these cells
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