Uterine atlas can lead to better models of the womb, provide insights into diseases

Endometrial organoids are clusters of cells that mimic the inner lining of the h
Endometrial organoids are clusters of cells that mimic the inner lining of the human uterus. Cells’ membranes are shown in purple and nuclei are shown in blue

In the quest to study the womb and its role in reproductive health, researchers in the Turco lab and their collaborators have generated a cellular map of the human uterus and of endometrial organoids — lab-grown models of the womb’s lining. The atlas, which is the most detailed of its kind, will help scientists to develop better models of the womb. The work could provide new insights into the healthy uterine tissue as well as into infertility, uterine cancer and other conditions.

Every month throughout her reproductive life, except during pregnancy, a woman sheds her entire endometrium — the womb’s inner lining — and regrows it. Due to the regenerative capacities of the human endometrium, studying the uterus has proved challenging, since endometrial tissues change periodically in response to female hormones.

Now, Konstantina Nikolakopoulou, a PhD candidate in the lab of Margherita Yayoi Turco , and her collaborators have generated the most detailed map of the human uterus to date. The atlas reflects the changing structure of the endometrium during the menstrual cycle and will help scientists to explore the types of cells that make the human uterus, and how they contribute to the organ’s function.

The researchers also profiled lab-grown miniature models of the endometrium called endometrial organoids and found that they accurately mimic many of the features of the womb’s lining.

"We know very little about how the normal endometrium is regulated and what it looks like," Turco says. The new study, she adds, indicates that endometrial organoids are a powerful tool to understand how the healthy uterus works and what goes awry in conditions such as infertility and endometriosis, a chronic disorder in which the endometrium grows outside of the uterus. Infertility affects millions of women of reproductive age worldwide, and one in 10 women suffer of endometriosis. Both conditions are often extremely distressing.

The study was done in collaboration with Roser Vento-Tormo, Omer Bayraktar, Sarah Teichmann and their teams at the Wellcome Sanger Institute in Cambridge, UK.

Mapping the womb Advanced techniques to profile gene expression in single cells have made it easier to identify the different cell types that make up the womb lining. But it’s remained difficult to map those cell types onto the intact uterus.

Using uterine samples from women of reproductive age, the researchers charted gene expression in individual cells and then mapped the location of different cell types within the uterine tissue. This allowed the team to generate the most detailed cellular atlas of the human uterus to date. The atlas is publicly available as a browsable web resource.

Because post-mortem tissues were included in the analyses, the researchers could characterize deep layers of the uterus that haven’t been explored in previous studies. What’s more, the team profiled tissues from different stages of the menstrual cycle, including the first half of the cycle, when stem cells proliferate in the endometrium, as well as the second half of the cycle, when endometrial cells become fully differentiated.

"We could really see how cell populations change and where they are located within the uterus," Turco says.

This huge amount of information could help provide answers to some of the questions that have puzzled scientists for decades — such as how the human endometrium regenerates after breaking down periodically. "Now we can look into the stem cell population to try to understand how this tissue regenerates itself," Nikolakopoulou says.

Nikolakopoulou, Turco and their colleagues also identified the molecular signatures that characterize key cell states in the human uterus. The researchers pinpointed two new cell states that become more numerous as the womb lining regenerates during the menstrual cycle. An analysis of samples from women with endometrial cancers and endometriosis revealed that those carrying a higher proportion of one of these cell states tend to have more severe disease.

Finally, the team profiled endometrial organoids derived from three healthy women. Small groups of cells from uterus biopsies can be made to grow into three-dimensional structures that resemble the womb lining. These organoids respond to female hormones and other molecular signals, mirroring the structure and function of the endometrium, the researchers found.

Next, Turco plans to use this knowledge to build models of the human womb that could provide valuable insights into health and disease. She explains that uterine organoids obtained using current protocols contain a mixture of cell populations. Her team is now trying to derive uterine organoids that contain only one type of cells, as this would help to understand some reproductive conditions.

"In some cases, it’s unclear why women are unable to get pregnant or if they do, why they may develop complications of pregnancy," Turco says. She notes that knowing the type of molecular signals that drive the formation of specific cell types will help researchers to develop better protocols for generating organoids. "That way, we could have more assays to probe how the endometrium of women with different disorders behave." Such organoids could also be used for testing potential treatment approaches, she says.

The uterus is part of the female reproductive system, and its inner lining is called the endometrium. In women of reproductive age, the endometrium goes through a process of remodeling, shedding, and regeneration that lasts about a month. If no fertilized egg attaches to the uterine wall, decreasing levels of the female hormones estrogen and progesterone result in menstruation, during which the endometrium is shed out of the body through the vagina. In the proliferative phase, estrogen causes the endometrium to thicken, and long tubular glands span from the surface, or luminal epithelium, to the inner tissue. Following ovulation, progesterone induces the secretory phase, during which the endometrial glands produce secretions that play important roles in pregnancy. Image credit: Konstantina Nikolakopoulou.

Original publication: Luz Garcia-Alonso*, Louis-François Handfield*, Kenny Roberts*, Konstantina Nikolakopoulou*, Ridma C. Fernando, Lucy Gardner, Benjamin Woodhams, Anna Arutyunyan, Krzysztof Polanski, Regina Hoo, Carmen Sancho-Serra, Tong Li, Kwasi Kwakwa, Elizabeth Tuck, Valentina Lorenzi, Hassan Massalha, Martin Prete, Vitalii Kleshchevnikov, Aleksandra Tarkowska, Tarryn Porter, Cecilia Icoresi Mazzeo, Stijn van Dongen, Monika Dabrowska, Vasyl Vaskivskyi, Krishnaa T. Mahbubani, Jong-eun Park, Mercedes Jimenez-Linan, Lia Campos, Vladimir Yu. Kiselev, Cecilia Lindskog, Paul Ayuk, Elena Prigmore, Michael R Stratton, Kourosh Saeb-Parsy, Ashley Moffett, Luiza Moore, Omer A. Bayraktar†, Sarah A. Teichmann†, Margherita Y. Turco†, Roser Vento-Tormo† Mapping the temporal and spatial dynamics 1 of the human endometrium in vivo and in vitro Nature Genetics (2021). Advance online publication.
*co-first authors
† co-senior authors

The Uterine Cell Atlas is part of the Human Cell Atlas initiative , a collaborative project to map all cell types in the human body.

About the co-first author Konstantina Nikolakopoulou hails from Volos, on the east coast of Greece. She got a Bachelor’s in biochemistry and biotechnology from the University of Thessaly, Greece, and a Master’s in molecular mechanisms of disease from Radboud University, the Netherlands. In 2018, she joined the Turco lab (previously based in Cambridge, UK) as a Master’s student, and then stayed on to work as a research assistant until she started her PhD in October 2020. She’ll join the FMI later this year to continue her PhD. Konstantina likes swing dancing, traveling and hunting for cute cafés with friends. Last year, she tutored pupils in schools impacted by the COVID pandemic.