Exploring the black box of human reproduction: endometrial organoids and assembloids - generation, implantation modeling, and future clinical perspectives.

One of the critical processes in human reproduction that is still poorly understood is implantation. The implantation of an early human embryo is considered a significant limitation of successful pregnancy. Therefore, researchers are trying to develop an ideal model of endometrium in vitro that can mimic the endometrial micro-environment in vivo as much as possible. The ultimate goal of endometrial modeling is to study the molecular interactions at the embryo-maternal interface and to use this model as an in vitro diagnostic tool for infertility. Significant progress has been made over the years in generating such models. The first experiments of endometrial modeling involved animal models, which are undoubtedly valuable, but at the same time, their dissimilarities with human tissue represent a significant obstacle to further research. This fact led researchers to develop basic monolayer coculture systems using uterine cells obtained from biopsies and, later on, complex and multilayer coculture models. With successful tissue engineering methods and various cultivation systems, it is possible to form endometrial two-dimensional (2D) models to three-dimensional (3D) organoids and novel assembloids that can recapitulate many aspects of endometrial tissue architecture and cell composition. These organoids have already helped to provide new insight into the embryo-endometrium interplay. The main aim of this paper is a comprehensive review of past and current approaches to endometrial model generation, their feasibility, and potential clinical application for infertility treatment.