Organoids from women’s endocrine-reproductive system and derived embryo...

Organoids from women’s endocrine-reproductive system and derived embryo implantation models, amenable to reprotoxicity screening

Department of Development and Regeneration, Cluster of Stem Cell and Developmental Biology, Unit of Stem Cell Research (Lab. Tissue Plasticity in Health and Disease), KU Leuven (University of Leuven), Leuven, Belgium

The inner lining of the uterus (endometrium) is the first contact site of the embryo and crucial for human reproduction. Knowledge on molecular and cellular mechanisms underlying the endometrium’s menstrual cycling and its embryo receptivity and interaction remains poor, as well as on how these processes go awry in endometrial pathology and under the influence of drugs and environmental pollutants like endocrine-disrupting chemicals (EDCs). This limited understanding is primarily due to a lack of reliable and robust research and screening models.

Organoid technology provides an innovative and powerful tool to grow high-fidelity miniature tissues in a dish. We established organoid models from both healthy and diseased endometrium which reproduce key features of the original tissue’s epithelium (Boretto et al., Development 2017; Nature Cell Biology 2019). In addition, the organoids show long-term expansion capacity while remaining genomically, transcriptomically and functionally stable. Endometrium-derived organoids phenocopy physiological responses to reproductive hormones and mimic the menstrual cycle ‘in the dish’. Organoids from endometrial diseases (endometriosis, PCOS, cancer, …) recapitulate characteristics of the patients' diseased tissue and faithfully capture the clinical heterogeneity. Recently, we combined this endometrial organoid model with stem-cell derived blastocyst mimics (blastoids) to construct a pioneering in vitro human implantation model, and found that it reliably captures the first events of pregnancy (Kagawa et al., Nature 2022). Now, these established models as well as further advanced microfluidic organ(oid)-on-chip systems, provide powerful tools to study multiple aspects of reproductive (patho)biology including endometrium receptivity and (in)fertility as well as its endocrine (dys)regulation. Moreover, the organoids can be harnessed into (personalized) drug screening platforms, as well as into reprotoxicity screening tools to assess the impact of all sorts of chemical compounds, as for instance present in food, environment and medicines, on women’s endocrine-reproductive health and fertility, to date still performed using poorly translatable animals.