Organoids to model the endometrium: implantation and beyond.

Despite advances in assisted reproductive techniques in the 4 decades since the first human birth after in vitro fertilisation, 1-2% of couples experience recurrent implantation failure, and some will never achieve a successful pregnancy even in the absence of a confirmed dysfunction. Furthermore, 1-2% of couples who do conceive, either naturally or with assistance, will experience recurrent early loss of karyotypically normal pregnancies. In both cases, embryo-endometrial interaction is a clear candidate for exploration. The impossibility of studying implantation processes within the human body has necessitated the use of animal models and cell culture approaches. Recent advances in 3-dimensional modelling techniques, namely the advent of organoids, present an exciting opportunity to elucidate the unanswerable within human reproduction. In this review, we will explore the ontogeny of implantation modelling and propose a roadmap to application and discovery.

Lay summary: A significant number of couples experience either recurrent implantation failure or recurrent pregnancy loss. Often, no underlying disorder can be identified. In both cases, the interaction of the embryo and maternal tissues is key. The lining of the womb, the endometrium, becomes receptive to embryo implantation during each menstrual cycle and provides a nourishing and supportive environment to support ongoing pregnancy. It is not possible to study early pregnancy directly, therefore, modelling embryo-endometrium interactions in the laboratory is essential if we wish to understand where this goes wrong. Advances in the lab have resulted in the development of organoids in culture: 3D cellular structures that represent the characteristics of a particular tissue or organ. We describe past and present models of the endometrium and propose a roadmap for future work with organoid models, from fundamental understanding of the endometrial function and implantation processes to the development of therapeutics to improve pregnancy outcomes and gynaecological health.