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Opening the Black Box of Human Implantation

NOMIS Project 2023

— 2028

For the first nine months of our lives, we had an essential, physical connection to our mothers. We were free-floating for the first eight days, and then we implanted in the uterus. This was a very difficult transition: Failure to implant accounts for up to 60% of pregnancy losses. Yet, little is known about this stage of development because, by its very nature, the embryo is inaccessible to observation during this time. Illuminating the journey from a fertilized single cell to a complex structure with multiple cell types is essential to understanding the beginning of life and discovering how this journey sets the stage for proper development. It will lead to potential clinical interventions for many diseases, from developmental disorders to infertility.

The project Opening the Black Box of Human Implantation will build upon two previous breakthroughs made by the project’s researchers: culturing natural mammalian embryos through implantation stages in a dish and generating synthetic mouse embryos from embryonic and extra-embryonic stem cells. The researchers will explore how the first cell fate decisions are made in natural human embryos by determining how the genome and transcriptome change from pre- to post-implantation in culture. This will enable them to build the first synthetic human implantation embryo model from stem cells. Using this model, they can study how the body plan is determined, employing approaches that are impossible at these stages with natural human embryos, such as CRISPR-Cas9 gene editing. The researchers will also generate endometrial organoids to recreate the lining of the uterus and build a new maternal implantation niche in vitro. Together, these systems will make possible the investigation of crucial but unknown crosstalk at the maternal–fetal interface and between the emerging embryonic lineages that is essential for successful development and pregnancy.

The researchers anticipate generating combined endometrial–embryo cultures that will support the development of human embryos within a maternal implantation niche, until the anterior–posterior axis first forms. They aim to uncover the signaling, transcriptomic, epigenomic and mechanical determinants of cell fate until the emergence of the organism’s body plan at gastrulation. This research will recreate and reveal a period of human development that has been entirely inaccessible, enabling the investigators to discover the key pathways and events that govern its success or failure.

The Opening the Black Box project is being led by Magdalena Zernicka-Goetz at the California Institute of Technology (Caltech; US) and the University of Cambridge (UK).

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