Shaping the human embryo for uterus implantation – HU_BLAST

Wider context:
Upon fertilization, the human conceptus floats down the uterus while undergoing rounds of cell divisions. This leads to the formation of a multicellular structure termed blastocyst that comprises an inner cluster of about 10 cells, the future foetus (Epiblast, Epi) and yolk sac (Hypoblast, Hypo), surrounded by an epithelial layer of trophoblasts (trophectoderm, TE) that 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 (inducers) that gatekeep the potential for trophoblasts to implant in utero.

Current limitations and proposed solutions:
Studying human early embryogenesis is challenging due to the limited availability of embryos and to the difficulty to manipulate them physically and genetically. There is thus a compelling need for in vitro alternatives to the use of embryos for research, 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. My lab has developed a model of the early human embryo, termed blastoid, which forms by self-organization of stem cells, can be generated in virtually infinite numbers, and is capable to interact specifically with hormonally-stimulated endometrial cells in vitro, thus recapitulating aspects of the initial steps of implantation.

Hypotheses/research questions:
Here, we hypothesize that using single cell RNA sequencing data from human blastocysts and human blastoids can reveal the functions of epiblast inducers and transcription factors during trophectoderm development and implantation.

Objectives:
The objective is to (1) delineate the molecular markers and signaling pathways that drive the transition of trophoblasts at the time of implantation, (2) measure their impact on trophectoderm development (proliferation, self-renewal, adhesion, invasion), and (3) reveal their functional role to mediate 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 molecular mechanisms underlying blastocyst development and implantation in order to guide clinical practices. Currently, during IVF procedures, only 40% of the fertilized eggs placed in culture reach a blastocyst stage with quality standards sufficient for in utero transfer, and 50% of these blastocysts fail to implant. Knowledge of the molecules acting during trophectoderm development could be used to complement IVF culture media and enhance IVF blastocyst quality and potential.