The most comprehensive cell atlas to date of the human uterus has uncovered two new epithelial cell states that can help distinguish between two forms of uterine cancer.
The human uterus
The lining of the human uterus (endometrium) is the site of implantation that provides the placenta nutritional support during pregnancy. Unlike other mucosal tissue, the endometrium undergoes dynamic, cyclical changes of shedding, regeneration and differentiation throughout reproductive life. Dysfunction to this underpins many common disorders, including uterine bleeding, infertility, miscarriage, pre-eclampsia, endometriosis and endometrial carcinoma. One in three women will suffer from some form of reproductive disease during their lifetime. In order to understand how the normal endometrium is regulated, it is important to dissect the mechanisms that regulate cellular differentiation across the menstrual cycle.
Combining single-cell and spatial transcriptomics to create a uterine cell atlas
In a recent study, published in Nature, researchers combined single-cell and spatial transcriptional profiling to create a reference map of the uterus. More specifically, the researchers aimed to interrogate the cellular states and spatial localisation of human endometrial cells during the menstrual cycle. They analysed uterine samples from 15 women of reproductive age to generate these maps.
From this, the researchers were able to dissect the signalling pathways that determined the cell fate of epithelial lineages. They defined a complementary role for WNT and NOTCH signalling in regulating differentiation toward the two main epithelial lineages – ciliated and secretory.
They also identified two new cell states: SOX9+LGR5+ and SOX9+LGR5-. These cell states became more prevalent as the epithelium regenerated during the menstrual cycle. The relative populations of these two cells were connected with two types of endometrial cancer. Tumours carrying a higher proportion of SOX9+LGR5+ were associated with more severe disease.
Generating organoid cultures
Alongside these single-cell and spatial reference maps, the team also generated three-dimensional endometrial organoid cultures. They used these organoids to characterise hormonal responses in vitro. When the group modulated WNT and NOTCH pathways in these organoid cultures, they were able to develop lineage-specific endometrial epithelial cells. They were also able to define the molecular events involved in their response to ovarian hormones.
These insights could help in the development of treatments for these common conditions that affect so many women in their lifetime.
Dr Sarah Teichmann, senior author, said:
“Although around one in three women will suffer from some form of reproductive disease during their lifetime, we know very little about these conditions, partly due to the challenges in analysing this highly dynamic and complex tissue. This Uterine Cell Atlas, and the sophisticated organoid models that have been created using these data, will help us to better understand the healthy endometrium and how things go wrong in disease. This study is part of the Human Cell Atlas and could also help to create better diagnostics to improve treatment outcomes for endometrial disorders.”
Image credit: canva