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Trophoblast cell migration into maternal tissues

PhD project

 

Laboratory for Primate Embryogenesis

 

Thorsten E. Boroviak

 

In the early stages of human pregnancy, the embryo implants into the uterus. This process is initiated by the outer cells of the embryo, the trophoblast, which attaches to the mother’s uterine wall. Trophoblast cells are invading into the uterus to form the placenta, a pivotal organ connecting the mother to the embryo and providing nutrition of the developing baby.

 

In 1 out of 533 births, the trophoblast grows excessively throughout the uterine tissue layers. It 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. Two thirds of cases remain undetected until delivery, leading to death rates of up to 7% despite state-of-the-art medical intervention.

 

Placenta accreta spectrum disorders have been linked to previous injuries of the uterus, including caesarian sections. As caesarian sections are increasingly performed over the last decades, this leads to a significant risk for pregnant women. Trophoblast cells sense the injury in the uterus as a niche, which promotes deeper trophoblast invasion into the uterus compared to healthy pregnancies. However, the exact mechanisms and signalling pathways controlling cell migration in vivo remain elusive.

 

In this project, we will determine what triggers trophoblast cell migration into the maternal tissues and how the mother’s uterine cells are controlling the depth of invasion. 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. All required ethical permissions and animal licenses are in place and have been reviewed and approved by the Wellcome Trust and NC3R. Samples have been successfully collected and profiling techniques are up and running in the lab. This provides a unique opportunity to illuminate the maternal – embryonic interface at the molecular level and utilize this information to tackle pathological trophoblast invasion.

 

In a second step, we will establish 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 provides a framework to identify early onset biomarkers in maternal blood serum in the near future. Results from our interdisciplinary model of trophoblast invasion in vitro may provide the basis for clinical intervention in the most severe cases of placenta accreta spectrum disorders.