Supervisor: Thorsten Boroviak
Co Supervisor: TBC
Project 1: Determining the essential regulators of primate trophoblast invasion to tackle placenta accreta spectrum disorders
Embryo implantation is initiated by the trophoblast, which attaches to the mother’s uterine wall. In 1 out of 533 births, the trophoblast grows excessively throughout the uterine tissue layers and can even break through the uterus and enter the abdominal peritoneal cavity. These placenta accreta spectrum disorders cause severe bleeding of the mother at birth, and may require the removal of the entire uterus – however the mechanisms of trophoblast invasion have remained unclear. In this project, we aim to identify the elusive factors which trigger trophoblast cell migration into the maternal tissues and investigate how the mother’s uterine cells control invasion depth.
To address these questions, we will first delineate in vivo primate embryo implantation in the marmoset. Building on strong collaborations with primate-centers in Germany and Japan, we will carry out genome-wide genetic and epigenetic profiling on early implantation stages. This can only be done in a non-human primate, because human embryos at this stage cannot be used on ethical grounds.
In a second step, we will take advantage of newly established marmoset trophoblast stem cell lines. We then focus on differentiation of these cells into placenta-forming cell populations of the postimplantation embryo. In collaboration with Dr. Kristian Franze’s lab with expertise in the generation of chemically defined 3D-hydrogels, differentiating trophoblast cells will be subjected to candidate agonists and antagonists of trophoblast invasion. Importantly, candidate factors will be narrowed down based on our in vivo profiling dataset, thus ensuring physiological relevance of the in vitro model.
This project is the first one to unravel the initial stages of primate placental development in vivo. Determining the secreted factors regulating initiation of trophoblast invasion may provide a framework to identify early onset biomarkers in maternal blood serum in the near future.
Project 2: How to build a primate: towards a synthetic model for primate embryogenesis
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.
Relevant references:
1. Boroviak, T., Nichols, J., 2017. Primate embryogenesis predicts the hallmarks of human naive pluripotency. Development.
2. 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.