A harmonized cell map of the human endometrium. Source: Nature Genetics (2024). DOI: 10.1038/s41588-024-01873-w
The most comprehensive map of the endometrium, the membrane that lines the uterus, has been created, revealing diverse cell types and detailing the dynamic changes these cells undergo during the menstrual cycle.
“Covering the most extensive range of menstrual cycle phases to date, this atlas will reveal new insights into the function of the endometrium and inform women's health research. Created by researchers from the Wellcome Sanger Institute, the Nuffield Department of Women and Reproductive Health at the University of Oxford, and collaborators, the atlas may in future help to study, understand and even treat diseases such as endometriosis.”
The study, published in Nature Genetics, is part of the broader “Human Cell Atlas” project to map every cell type in the body in order to transform our understanding of health and disease.
Linking them to genetic mutations known to increase the risk of endometriosis, the researchers discovered two types of immune cells and two types of stromal cells that may be involved in the disease, highlighting new avenues for future research.
The Human Endometrial Cell Atlas, now publicly available in an accessible, interactive format, is expected to become a valuable central resource for researchers studying the endometrium and will also be used to inform and develop more effective experimental models.
A detailed map of the endometrium could provide researchers with insight into the unique cells and interactions not found in other parts of the body, and provide a better understanding of tissue changes during the menstrual cycle, including the endometrium's ability to regenerate without leaving scars.
The endometrium is crucial for human reproduction, supporting pregnancy if a fertilized egg implants, or sheds and regenerates each month without leaving a scar if implantation does not occur. This constantly changing tissue undergoes complex and dynamic changes throughout the menstrual cycle, making it extremely challenging to study.
Endometrial disease affects millions of people worldwide. Endometriosis is a chronic condition in which endometrial-like cells grow outside the uterus and is the second most common gynecological condition in the UK. It can cause debilitating pain and fertility problems, among other symptoms. There is currently no cure and the cause of the disease is unknown.
Previous studies investigating the human endometrium and uterus have provided limited images, but none have captured all the stages that the endometrium goes through throughout the menstrual cycle.
This new endometrial cell atlas was led by researchers from the Wellcome Sanger Institute and the Nuffield Department of Women and Reproductive Health at the University of Oxford, who generated new data on 74 endometrial samples, which they harmonized with existing single-cell data from 47 individuals.
The atlas contains data from approximately 626,000 cells from 121 people with or without endometriosis, both during their natural menstrual cycle and while taking hormonal contraceptives.
The team discovered several new cell types that are only present at certain times in the menstrual cycle in response to hormone levels. The cellular responses to hormone levels are essential for menstrual cycle progression and fertility, and these cells may represent promising therapeutic targets for diseases associated with hormone disruptions, such as fertility disorders.
The researchers uncovered interactions between immune cells called macrophages, a type of connective tissue cell known as stromal cells, and blood vessel cells that are involved in regenerating the endometrium without leaving a scar. Understanding how these pathways are inhibited in common menstrual symptoms such as abnormal bleeding, where the endometrium keeps shedding, could help identify new ways to intervene.
No significant differences in the number of cell types were found between endometriosis and non-endometriosis patients, although slight differences in the proportion and gene expression of some cells were found in endometriosis patients. These results are consistent with previous studies, but this atlas provides a more detailed view of the specific cell types that may be dysregulated in endometriosis.
To investigate the effects of genetic variants previously linked to endometriosis, the researchers combined detailed cell maps of the endometrium with large-scale genome-wide association studies.
The team focused on four cell types that were likely to be dysregulated by these genetic changes: They also found that certain signaling pathways between some stromal and structural cells were dysregulated in endometriosis patients, and these signaling pathways are known to be necessary for the progression of the menstrual cycle.
This study highlights that these cell types and signaling pathways may be involved in endometriosis and may aid future studies investigating how genetic changes are linked to the disease.
“Having this detailed and large-scale genomic resource on the endometrium is invaluable to fully understand how it functions in health and what happens in conditions such as endometriosis.
“The development of a non-invasive diagnostic test and effective treatment for this debilitating disease has been a top priority for clinicians, researchers and endometriosis patients around the world.
“Although further research and validation is needed, our study suggests that certain cells and pathways are dysregulated in endometriosis which, if replicated in additional studies, could represent potential targets for diagnosis and treatment in the future,” says Dr. Magda Maréková.
“Creating an integrated human endometrial cell atlas will translate all data into one language that researchers around the world can speak. We hope this atlas will be an important stepping stone towards building a future endometrial atlas that will include information on all health conditions across the lifespan.”
“Further studies collecting additional health information, such as whether an individual's periods are regular or whether they have been pregnant before, as well as genomic data, could help build the atlas and further investigate factors that may influence uterine health and the development of endometrial disease,” says Dr Luz García Alonso.
“The human endometrium has been largely ignored in large-scale cellular studies of different parts of the body. Having a large-scale, freely available, and growing, single-cell human endometrial atlas will enable important new research into understanding and treating diseases that are unique to women and those born with a uterus, such as endometriosis,” says Professor Clina Zondervan.
“The human uterus is a dynamic and poorly understood part of the body that holds important information that can be used to treat a variety of diseases. Understanding how hormones affect the endometrium and being able to map all of the changes during the menstrual cycle has never been possible before and would not have been possible without the people who generously donated their endometrial tissue for research.”
“We have been able to uncover unique interactions and cells that can inform research models, investigate possible causes of the disease and create a resource that can be freely used worldwide to help develop new treatments for people suffering from endometrial diseases,” says Dr Roser-Went-Tormo.
Further information: Magda Marečková et al. “An integrated single-cell reference atlas of the human endometrium.” Nature Genetics (2024). DOI: 10.1038/s41588-024-01873-w
Courtesy of the Wellcome Trust Sanger Institute
Source: Human endometrial map uncovers hidden clues to health (August 28, 2024) Retrieved August 28, 2024 from https://medicalxpress.com/news/2024-08-human-endometrial-uncovers-hidden-health.html
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