Article written by Marie Moullet, PhD student at the Wellcome Sanger Institute.
The most important moment of your life happens when you are a tiny embryo. You attach to the wall of your mother’s uterus, to a tissue called the endometrium, which provides you with oxygen and nutrients to develop into a healthy baby. Using a technology called organoids, it is now possible to study the endometrium in health, disease and early stages of pregnancy in the lab.
Organoids are miniature organs in a dish, where multiple cell types grow together in 3D to mimic the biology of the tissue of origin (Zhao 2022). Tissue-specific stem cells are placed in a scaffold that provides structural support, nutrients and signalling factors to help cells grow. Endometrial organoids were first established in 2017 by using a cocktail of growth factors and hormones mimicking the menstrual cycle to help cells divide into endometrial cells (Turco 2017). They are a particularly exciting technology because the combination of 3D structure and presence of different specialised cells makes the cells in the lab more similar to cells in human, therefore more biologically and clinically meaningful.
Endometrial organoids have the potential to revolutionise reproductive and women’s health in coming years. The endometrium remains poorly understood despite its fundamental importance. This is partly due to historical lack of funding for the study of reproductive tissues. Additionally, the endometrium sheds and regenerates each month as part of the menstrual cycle. This variation means we need many more samples to study each phase of the cycle. Finally, the endometrium is particularly challenging to study in the lab: traditional methods involving growing cells in a flask may miss important aspects of endometrial biology (due to the limitation to a single cell type and lack of 3D structure), and insights from other animals frequently used in research such as mice are limited (only certain primates menstruate (Bellofiore 2019)). The emergence of endometrial organoids is an exciting solution for this challenge.
Endometrial organoids will help us better understand fertility and infertility. Scientists can now grow organoids that not only include multiple endometrial lineages, they can also grow them with a blastoid, a group of cells resembling a human embryo of ~200 cells, to observe the very initial steps of embryo implantation (Shibata 2024). This is a key innovation because cell-cell interactions at such early stages of development are largely impossible to observe in humans due to ethical and technological limits. Ethical constraints also prohibit the type of targeted perturbation experiments scientists use to decipher biological events. Organoids allow scientists to test implantation outcomes under different genetic or chemical perturbations in a system that is as close to humans as possible.
Additionally, organoids can be grown using cells from patients with recurrent implantation failure (RIF), patients who do not reach pregnancy after multiple cycles of in vitro fertilisation (IVF) (Zhang 2023). Understanding differences in the endometrium of patients with and without RIF is the first step towards identifying solutions and improving the rate of IVF success.
Endometrial organoids are also important for understanding and treating endometrial diseases. For example, endometriosis is a debilitating disease associated with chronic pain and problems with fertility, periods, and digestion. It is estimated to impact the lives of 10% of women of reproductive age, and women with endometriosis are twice as likely to experience infertility. Yet, the cause of the disease remains unknown, diagnosis can take up to 10 years, and there is currently no cure (Zondervan 2020). The disease is characterised by the presence of endometrial-like cells (called lesions) outside the uterus. There is increasing evidence that the most pronounced cellular changes in endometriosis are present in the lesions rather than the endometrium itself (Riaz 2024). Growing organoids from endometriosis lesions will therefore allow exploration of the biological changes driving lesion formation.
New drugs are needed to help treat infertility and diseases such as endometriosis. Endometrial organoids offer a promising platform for drug screening and drug development. The more similar lab-grown cells are to human tissue, the more likely it is that preclinical drug screens will prove successful when tested in humans. Having a clinically relevant system in the lab overcomes some of the ethical and logistical challenges of testing a large number of compounds in animals. Growing organoids from patients with specific conditions and capturing inter-individual variation may help predict individual response to drug treatment. The use of organoids to capture patient-specific effects is already being used in multiple cancers (Verduin 2021), including endometrial cancer (Borreto 2019). The innovative use of organoids in drug screening promises to accelerate the discovery of new therapies and enhance our understanding of endometrial biology and disease.
Scaling the size of organoid platforms will shape reproductive health sciences for the next 25 years as scientists can explore an increasing number of conditions and inter-individual variability of the endometrium. The first endometrial organoids were grown from cells isolated from the endometrium during a biopsy, an invasive procedure which must be carried out by a trained clinician. It is now possible to grow organoids using cells obtained from menstrual blood (Cindrova-Davies 2021). Using patient samples obtained through non-invasive procedures facilitates the collection of a larger number of samples. As the process of growing organoids becomes more accessible and cost-effective, it paves the way for personalised medicine. This advancement increases the likelihood that, in the future, we will be able to create models based on an individual's specific cells. In a therapeutic context, this means we can better understand which drugs will be most beneficial for each person.
The endometrium supports the early stages of life, and organoids support endometrium research. From the very early stages of life to complex debilitating disease in adulthood as in endometriosis, there remain huge gaps in our understanding of this fascinating tissue. Endometrial organoids are a unique opportunity to fill these knowledge gaps and improve female reproductive health in the coming decades.
References
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