A drug discovery platform for early human embryogenesis.

The first weeks of human embryonic development are crucial. Early abnormalities or insults result not only in infertility, but also contribute to long-term impairment of human health (e.g. cardiovascular disease and diabetes). Managing the onset of pregnancy therefore offers a huge opportunity to improve public health through effective family planning and disease prevention. To better manage pregnancy, biomedical research would require large numbers of human embryos for use in genetic and drug screening. Unfortunately, however, the scarcity of human embryos makes this impossible. Recently, hope for an alternative approach has come from work in my lab showing that mouse stem cells self-organize into structures closely resembling pre-implantation embryos (a.k.a. blastocysts), that we termed blastoids. Because stem cells can be largely expanded and genetically-modified, these embryo models provide a scientifically powerful, and ethical alternative to the use of embryos for research, one that is amenable to drug and genetic screens, thus opening numerous possibilities for therapeutic breakthroughs. Here, during this ERC-CoG, we have been developing human blastoids and uterine organoids to model embryogenesis and uterine implantation in vitro. This platform is currently being used to identify potential targets for the therapeutic modulation of the molecular pathways that control (1) early embryogenesis and (2) interactions between the embryo and uterus, and will therefore pave the way to (3) establishing a drug discovery pipeline for the management of implantation. This project will generate key insights into druggable molecules controlling early human embryogenesis, facilitating identification of therapeutic targets to improve in vitro fertilization (IVF) procedures and contraception and, ultimately, to prevent several chronic diseases.

1- Development of human blastoids and dissemination of the method via Open access publications of the original research and of the detailed protocols.

Human blastoids model blastocyst development and implantation. Kagawa H, Javali A, Khoei HH, Sommer TM, Sestini G, Novatchkova M, Scholte Op Reimer Y, Castel G, Bruneau A, Maenhoudt N, Lammers J, Loubersac S, Freour T, Vankelecom H, David L, Rivron N. Nature. 2022 Jan;601(7894):600-605. doi: 10.1038/s41586-021-04267-8. Epub 2021 Dec 2. PMID: 34856602

Generating human blastoids modeling blastocyst-stage embryos and implantation. Heidari Khoei H, Javali A, Kagawa H, Sommer TM, Sestini G, David L, Slovakova J, Novatchkova M, Scholte Op Reimer Y, Rivron N. Nat Protoc. 2023 May;18(5):1584-1620. doi: 10.1038/s41596-023-00802-1. Epub 2023 Feb 15. PMID: 36792779 Review.

Protocol for Human Blastoids Modeling Blastocyst Development and Implantation. Kagawa H, Javali A, Heidari Khoei H, Sommer TM, Sestini G, Novatchkova M, Scholte Op Reimer Y, Rivron N. J Vis Exp. 2022 Aug 10;(186). doi: 10.3791/63388. PMID: 36036618

2- Development of an ethical framework for human embryology with stem cell-based embryo models.

Changing the public perception of human embryology. Rivron NC, Martinez-Arias A, Sermon K, Mummery C, Schöler HR, Wells J, Nichols J, Hadjantonakis AK, Lancaster MA, Moris N, Fu J, Sturmey RG, Niakan K, Rossant J, Kato K. Nat Cell Biol. 2023 Dec;25(12):1717-1719. doi: 10.1038/s41556-023-01289-4. PMID: 37985870

An ethical framework for human embryology with embryo models. Rivron NC, Martinez Arias A, Pera MF, Moris N, M'hamdi HI. Cell. 2023 Aug 17;186(17):3548-3557. doi: 10.1016/j.cell.2023.07.028. PMID: 37595564

Going high and low: on pluralism and neutrality in human embryology policy-making. Ismaili M'hamdi H, Rivron NC, Asscher EC. J Med Ethics. 2022 Dec 8:jme-2022-108515. doi: 10.1136/jme-2022-108515. Online ahead of print. PMID: 36600611

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Periodic Reporting for period 2 - BLASTOID (A drug discovery platform for early human embryogenesis.)

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