HU.BLAST - Shaping the human embryo for uterus implantation

Wider context: Upon fertilization, the human conceptus floats down the uterus while undergoing rounds of cell divisions to form a structure called a blastocyst. It comprises an inner cluster of about 10 cells, the future fetus (Epiblast, EPI), and the yolk sac, surrounded by an epithelial layer of trophectoderm (TE). This TE fulfills the crucial functions of mediating the implantation into the uterus and of forming the placenta. Our previous work showed that the development of the TE is controlled by signals produced by the EPI (called inducers) that gatekeep the potential to implant in utero but, in humans, these signals are unknown. Current limitations and proposed solutions: Studying human early embryos is challenging due to their limited availability and to the difficulty to manipulate them, both physically and genetically. There is thus a compelling need for in vitro alternatives; models that can be made widely available, are amenable to easy genetic manipulations and drug screens. Such human embryo models have a huge potential for biomedical discoveries. Our labs have developed a model of the human blastocyst, termed blastoid, that forms via stem cells self-organization, can be generated in virtually infinite numbers, and interacts specifically with hormonally-stimulated endometrial cells in vitro, thus recapitulating the initial steps of implantation. Hypotheses/research questions: Here, we hypothesize that single-cell RNA sequencing data from human blastocysts and functional assays in human blastoids can reveal the functions of EPI inducers, TE transcription factors, and attachment molecules acting upon implantation. Objectives: The objective is to (1) delineate the biological pathways that drive the transition of the TE at the time of implantation, (2) measure their impact on TE development, and (3) reveal their function in mediating the attachment to the endometrium. Level of originality/innovation: Human blastoids are embryo models that, when appropriately benchmarked, can contribute to a wide range of scientific and biomedical applications (infertility, contraception). We aim at using them to build a strong fundamental understanding of the mechanisms underlying blastocyst development and implantation to guide clinical practices. Currently, during IVF procedures, less than 40% of the fertilized eggs placed in culture form a blastocyst that implants in utero. Knowledge of the acting molecules could be used to complement IVF culture media and enhance IVF blastocyst quality and potential. Primary researchers involved: This proposal is led by Nicolas Rivron and in collaboration with Laurent David (Nantes Université, France).