More of a good thing is not always better – and certainly not if you are a stem cell
Stem cell research led by the Babraham Institute has uncovered key new knowledge about how placental stem cells switch between maintaining a stem cell identity to setting off down the route to becoming specialised cell types.
Intuitively, one would think that more of a good thing should be even better – specifically in the context of factors that maintain the self-renewing character of a stem cell. However, research from the Babraham Institute in association with the Centre for Trophoblast Research has found that this is certainly not the case for trophoblast stem cells from which the fundamental cell types of the placenta are derived. In looking at transcription factors – key orchestrators of the genes expressed in any given cell – the Babraham team observed that it is not simply their presence or absence that determines the stem cell state, but the finely tuned balance between them.
Two distinct populations of stem cells can be derived from the very early mammalian embryo; embryonic stem cells (ESC) which give rise to the embryo itself and their counterparts; trophoblast stem cells (TSCs) which give rise to major structures of the placenta.
In order to unpick the intricacies of the molecular mechanisms that underlie the self-renewal state of TSCs, the researchers used a multi-faceted approach looking at protein interactions, gene expression and genome binding. The researchers focused on three key transcription factors that they found interact physically with each other – Elf5, Eomes and Tfap2c. Each of these three factors is individually required to make a TSC. However, intriguingly, maintaining TSC identity did not simply depend on their sheer presence – it also critically depended on their relative abundance in proportion to each other. Thus, too much of Elf5 or Tfap2c in proportion to Eomes triggered TSCs to differentiate. The data reveal that the switch between retaining the self-renewing ability of TSCs and the onset of differentiation occurs when the triplet of transcription factors begins to operate as a duo.
Dr Myriam Hemberger, group leader in the Epigenetics programme at the Babraham Institute and senior author on the research paper published in Genes & Development said: “Our knowledge of the regulation of self-renewal and differentiation in trophoblast stem cells lags far behind that of ESCs yet this knowledge is critically important to better understand normal placental development – a prerequisite for embryo survival. Our insights reveal a role for Elf5 as a molecular switch governing the balance between TSC proliferation and differentiation, thereby explaining how the same transcription factors can drive different outcomes for the cell – simply by altering their relative abundance.
“At a practical level, our research explains why it is rather difficult to maintain mouse TSCs in culture and likely also why approaches to derive the same stem cell population from the human placenta have not been successful to date. Our work provides fundamental insights to facilitate that aim, a major goal that lies at the heart of our collaborative efforts with the Centre for Trophoblast Research”.
Better understanding of how placental stem cells are regulated will help researchers to identify and obtain these cells from human placentas. These would be a fundamentally important research tool to provide a better understanding of the earliest stages in pregnancy when the foundations for a functional placenta are laid down; importantly, it is these early phases in development that – when abnormal – underlie the most common pregnancy complications.
This research was supported by the BBSRC, Centre for Trophoblast Research, University of Cambridge and the Wellcome Trust.
Tissue section of a very early mouse embryo composed of the embryonic portion and the extra-embryonic trophoblast compartment, stained for three transcription factors (Elf5 - green, Eomes - red, Tfap2c - blue). The region where all three factors are found and interact as a complex is the trophoblast stem cell niche (dotted box). Outside that compartment, Elf5 and Tfap2c predominate and function as a duo in the absence of Eomes. This two-protein complex binds to different regions of the genome, turning on genes promoting differentiation and triggering the exit from the self-renewal cycle.
Associated researchers (in author order):
Paulina A. Latos, postdoctoral research scientist, Hemberger group, Epigenetics programme and Next Generation Fellow, Centre for Trophoblast Research, University of Cambridge
Arnold Sienerth, postdoctoral research scientist, Hemberger group
Alexander Murray, postdoctoral research scientist, Hemberger group
Claire Senner, postdoctoral research scientist, Hemberger group
David Oxley, Head of Mass Spectrometry facility
Sarah Burge, postdoctoral research scientist, Hemberger group
Myriam Hemberger, group leader, Epigenetics programme, member of the Centre for Trophoblast Research, University of Cambridge
Animal research statement:
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research presented here used a small number of genetically modified early-gestation embryos.
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Latos et al. (2015) Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks. Genes & Development