How to build a primate: towards a synthetic model for primate embryogenesis
Supervisor:Dr. Thorsten Boroviak
Web Page: https://boroviaklab.pdn.cam.ac.uk/
Cells of the early embryo are of particular interest for regenerative medicine, as they harbour the potential to form all cell types of the adult body. Although the mouse has been instrumental for our understanding of mammalian development, we now have to translate this knowledge into our own species to advance and pioneer biomedical research.
There are fundamental differences between rodent and primate embryonic development (Boroviak and Nichols, 2017), leaving gaps in our understanding of human development. Preimplantation development establishes three lineages at the late blastocyst stage: pluripotent epiblast and extraembryonic hypoblast and trophoblast. Upon implantation in rodents, the epiblast gives rise to a cup-shaped epithelium, the egg-cylinder. However, the primate epiblast undergoes an additional lineage decision and segregates extraembryonic amnion, before forming a flat embryonic disc. This has dramatic implications for our conceptional understanding of primate pluripotency: Mouse embryonic stem cells (ESCs) are restricted to embryonic lineages, while primate ESCs in an authentic developmental state give rise to both extra-embryonic amnion and embryonic disc.
In this PhD project, we aim to develop an in vitro model for primate embryogenesis. We will use bioengineering approaches to reconstitute the late blastocyst from non-human primate epiblast-, hypoblast- and trophoblast cultures in vitro. Epiblast-like cells will be obtained using recently established marmoset ‘reset’ ESCs cultures (manuscript in preparation). Based on our strong collaborations with Primate Centres in Germany and Japan, the PhD candidate will derive marmoset trophoblast and hypoblast cultures. He/She will be able to take advantage of the unique expertise at the Centre for Trophoblast Research for extraembryonic tissues and will be supported by our recent in vivo single-cell embryo transcriptome data in the marmoset, working in a multidisciplinary and stimulating environment.
The goal is to generate synthetic non-human primate embryos, assembled from in vitro cultured cells, and develop a model for implantation on hormone-responsive endometrial cells (Turco et al., 2017). Importantly, access to in vivo controls in the non-human primate system ensures that findings are developmentally relevant. This model will provide unprecedented insights into primate implantation and amnion formation, with far-reaching implications for cancer, stem cell biology and treatments for implantation failure.
Boroviak, T., Nichols, J., 2017. Primate embryogenesis predicts the hallmarks of human naive pluripotency. Development.
Turco, M., Gardner, L., Hughes, J., Cindrova-Davies, T., Gomez, M., Farrell, L., Hollinshead, M., Marsh, S., Brosens, J., Critchley, H., Simons, B., Hemberger, M., Koo, B., Moffett, G., Burton, G., 2017. Hormone-responsive organoid cultures of human endometrium Nat Cell Biol.
We are in the process of establishing a collaboration with Astra Zeneca to use small molecule libraries to capture authentic developmental states.