MTZ®-MPI-Award 2021 to Niraimathi Govindasamy

Almost half of the human pregnancies are discontinued at the time of implantation, according to clinical reports. However, the cellular mechanisms of implantation and the factor coursing termination of pregnancy are very poorly understood.

The process of implantation mediates the first direct interactions between the embryo and the mother. Specialized cells of the mouse embryo, known as trophoblast giant cells (TGCs), invade deep into the uterine tissues, enabling nutrient uptake and gas exchange with the maternal environment. In turn, the uterine stroma rapidly proliferates and completely engulfs the implanting embryo. Thus, studying the process of implantation is fundamentally challenging, as the embryo is concealed by the uterine tissues and its development depends on the maternal support.

To overcome this obstacle, Niraimathi Govindasamy, a doctoral student in the lab of Dr. Ivan Bedzhov, established a novel 3D culture system based on synthetic hydrogels, which mimic the biomechanical properties of the maternal tissues. “This approach enabled for the first-time direct observations of the implantation process in vitro and revealed that the TGCs, similar to certain types of cancer, form invasive strands, penetrating the surrounding environment,” Niraimathi Govindasamy says.

As an early miscarriage can be caused by insufficient blood supply to the implantation site, she asked whether there is a signalling crosstalk between the invading TGCs and the maternal vasculature. In collaboration with Hongyan Long from Dr. Britta Trappmann’s lab, she used a microfluidic chip to model the interactions between the embryo and the blood vessels. “When we cultured the embryos next to the endothelial cells, which were placed into the microfluidic channels of the chip, we saw that the invasive TGCs migrate towards the blood vessels and form direct cell-cell contacts” says Nirai. “This was truly fascinating!”

In addition, with the help of Dr. Hyun-Woo Jeong from Prof. Dr. Ralf Adams department, Nirai found that the TGCs gain expression of typical vascular genes, such as VE-cadherin, Dll4 and Pdgfr. “Thus, as the embryo invades the maternal tissues, the TGCs start expressing cell surface receptors, ligands and adhesion molecules, similar to the nearby blood vessels. Dissecting further this process, I identified that Pdgfr-signalling promotes the establishment of direct cell-cell contacts between the TGCs and the vasculature,” she says. As the Pdgfr-signalling has been previously shown to mediate the recruitment of pericytes to the endothelial cells, Nirai’s findings suggests that the TGCs exploit this pathway to locate the endothelial cells of the maternal blood vessels. Consequently, the expression of compatible cell adhesion molecules in the TGCs and the vasculature enables the formation of heterologous cell-cell contacts. This fundamental discovery has also a potential clinical importance, as it has been shown that treatment of chronic myeloid leukemia (CML) using a Pdgfr inhibitor, increases the risk of miscarriage in pregnant patients.

Taken together, Nirai’s work elucidated the hidden dynamics of the implantation process and revealed the cellular mechanism of the embryo’s first contact with the maternal vasculature. Although optimized for mouse embryos, the 3D biomimetic platform can serve as a blueprint for the future generation of culture environments that support the embryonic development of other mammalian species, further broadening our understanding of embryo-maternal interactions.

About Niraimathi Govindasamy