The earliest cell fate decision in development creates two distinct cell populations: trophoblast cells that go on to form the yolk sac and placenta, and embryonic cells that develop into the embryo itself and all subsequent cell types of the body. This very first lineage decision can be most effectively studied by using mouse stem cells representing these first two lineages, i.e. trophoblast (TS) and embryonic (ES) stem cells, respectively.
Over the past years we have learnt, in work that resulted in a Nobel Prize for Shinya Yamanaka and John Gurdon, that cells of the adult body can be reprogrammed back to a developmentally much earlier, ES-like state. However, the conditions to overcome the very first cell fate decision, which would enable an embryo-derived cell to functionally contribute to the placenta, had not been tested in great depth. Work by Babraham Institute researchers just published in the journal Nature Communications now shows that this earliest, most fundamental differentiation event in development between the embryonic and trophoblastic lineages is much more robust than previously appreciated.
Commitment to different cell lineages is in part due to cells acquiring distinct patterns of epigenetic marks that control which genes in the genome are expressed and which ones are stably repressed. Epigenetics refers to chemical modifications to DNA that do not affect its sequence but which affect gene expression. These marks fix the identity of the cell and prevent it from reverting into other cell types.
Although in the developing embryo, the decision between embryonic and placental trophoblast cells is irreversible, ES cells can be manipulated in experimental conditions to partially switch identities. The researchers, led by Dr Myriam Hemberger, assessed the effectiveness of a range of strategies to reprogramme ES cells to become TS-like cells, including expressing key transcription factors (proteins that control the expression of genes) that promote TS cell identity in ES cells, and switching on critical signalling pathways.
They demonstrated that the identity of ES cells cannot be fully overwritten and identified a vital set of genes that are epigenetically regulated and resistant to reprogramming, thereby preventing cross-over between the embryonic and trophoblast cell lineages. The epigenetic regulation of these core genes is central in perpetuating the first cell fate decision in early embryo development and determining the developmental potential of the two different stem cell populations.
Dr Hemberger, Group leader at the Babraham Institute, said: “This research contributes to our understanding of how cell identity is maintained in the first two cell lineages and why ES cells are resilient to reprogramming into placental trophoblast cells. These tight lineage-reinforcing barriers may serve to protect the embryo from accidentally forming trophoblast derivatives within its own tissues that would be fatal for its development.
“This work will help us drive forward the establishment of relevant models of early human trophoblast that will be instrumental for advancing our understanding of the most common pregnancy complications such as pre-eclampsia and fetal growth restriction.”
Image description:
ES cells reprogrammed for 5-6 weeks towards a TS-like fate by induction of the transcription factor Cdx2 and Raf signalling, stained for the TS cell transcription factors Cdx2 (green) and Elf5 (red). Nuclei are in blue. The co-expression of Cdx2 and Elf5 that is typical for true TS cells is unstable and frequently lost in these reprogrammed TS-like cells. Concomitant with that is a lack of true TS cell self-renewal potential.
Related content: For more on stem cell reprogramming see: Wiping the slate clean
Associated researchers (in author order):
Francesco Cambuli & Alexander Murray, PhD students and joint first authors (Hemberger Lab)
Wendy Dean, Senior research scientist
Dominika Dudzinska, PhD student (Hemberger Lab)
Felix Krueger, Bioinformatician
Simon Andrews, Head of Bioinformatics
Claire Senner, Postdoc researcher (Hemberger Lab)
Simon Cook, Group Leader, Signalling
Myriam Hemberger, Group Leader, Epigenetics