The most complete map of the endometrium covers the widest range of menstrual cycle phases ever described.
Researchers from the Wellcome Sanger Institute at the University of Oxford, UK, have developed the most comprehensive atlas of the human endometrium. Covering the widest range of menstrual cycle phases ever recorded, the map identifies different cell types and details the dynamic changes they undergo throughout the cycle. The findings, published in Nature Genetics, provide new insights into the functioning of the endometrium, offering valuable insights for women’s health research.
The study is part of the Human Cell Atlas project, which aims to map all cell types in the human body to revolutionize our understanding of health and disease. The researchers linked genetic variants associated with increased risk of endometriosis with two types of immune cells and two types of stromal cells potentially involved in the disease. This discovery opens up new avenues for future research into endometriosis.
This atlas of human endometrial cells available in an interactive and publicly accessible format. This resource is expected to become a key tool for researchers, facilitating the development of more effective laboratory models and advancing the study of the endometrium. In fact, having a detailed map of the endometrium gives researchers a unique view of the cells and their interactions that is not available anywhere else in the body. This atlas provides a deeper understanding of tissue changes during the menstrual cycle, highlighting the remarkable ability of the endometrium to regenerate without scarring. Knowing this is key to advancing our understanding of uterine health and related conditions.
“The human endometrium has been largely ignored in large-scale cell-based studies of various body parts, so having a free, large, and growing, atlas of single-cell human endometrium will enable important new research to understand and treat specific diseases such as endometriosis,” he noted. Krina Zondervan, co-author of the study.
Limited imaging of the endometrium
The endometrium enables pregnancy by providing an environment for the implantation of a fertilized egg. In the absence of implantation, this tissue is shed and regenerated every month, leaving no scars. Because of their complex and dynamic changes throughout the menstrual cycleHowever, endometrial examination was extremely challenging.
Endometrial diseases affect millions of women worldwide. Endometriosis affects about 190 million women and girls of reproductive age worldwideAccording to the World Health Organization (WHO), there is currently no cure and its exact cause remains unknown.
Previous studies of the endometrium and uterus have provided partial views of the tissue, but have never been able to fully capture all stages of the menstrual cycle. The new Endometrial Cell Atlas changes that by providing detailed data on 74 endometrial samples. These data were aligned with information obtained from individual cells from 47 individuals, resulting in an atlas covering approximately 626,000 cells from 121 individuals. This dataset includes samples from people with and without endometriosis, both during natural menstrual cycles and while using hormonal contraceptives.
New data
By carefully analyzing and spatially mapping more than 600,000 high-quality cells and nuclei from 121 individuals, the researchers significantly exceeded the number of donors and cells profiled in previous studies on individual endometrial cells. This extensive analysis allowed identify previously undescribed cellular statesas a population of CDH2+ (N-cadherin) epithelial cells. The genetic expression of these cells, their location in the basal glands, and their putative association with basal fibroblasts suggest that they may be the epithelial stem cells or progenitor cells described in previous studies. Transcriptomic profiling of these cells opens new avenues for studying their role in endometrial repair and regeneration, as well as in the pathophysiology of associated diseases, the study indicates.
In addition, the atlas reflects multiple transition states of cells previously undescribed, such as preluminal, preglandular, and decidualized stromal cell subpopulations during the early/mid secretory phase. This period is critical for preparing the endometrial receptivity in response to rising progesterone levels. A tightly regulated cellular response to changes in hormone levels is essential for the development of the menstrual cycle, tissue homeostasis, and fertility. Thus, the identified cellular states may offer new therapeutic targets for the treatment of endometrial and uterine diseases that involve abnormalities in hormonal signaling and cellular responses.
In addition to ovarian hormones, paracrine factors locally produced are critical to the progression of the menstrual cycle. The new atlas includes a detailed map and interactive platform that illustrates cell-cell interactions in vivo throughout the menstrual cycle, enriching existing knowledge that is largely based on in vitro cell cultures.
In this sense, a remarkable discovery is how TGFβ activity is regulated by different states of epithelial and mesenchymal cells both spatially and temporally. Detailed identification of in vivo signaling pathways associated with the menstrual cycle. opens up opportunities to improve endometrial organoid cultures, which are currently supplemented with TGFβ inhibitors. Incorporating spatial and temporal TGFβ signaling into these cultures may optimize physiological response and cellular differentiation, reducing differences between endometrial cells in vivo and in vitro.
The study also identified various interactions through which Uterine macrophages (UM) promote scarless endometrial regeneration.supporting previous studies that suggest a key role for UM in this process. These interactions are most evident during menstruation, highlighting the importance of microcirculation at this stage. Understanding whether disruption of these interactions contributes to common menstrual cycle disorders, such as abnormal uterine bleeding, may open up new avenues for the development of immunology-based treatments.
“Having this deep and large-scale endometrial genomic resource is invaluable if we want to fully understand how the endometrium functions in healthy conditions and what goes wrong in conditions like endometriosis,” he said. Magda Mareckova, co-author of the study“Developing a non-invasive diagnostic test and effective treatment for this disease has been a priority for doctors, researchers and people with endometriosis around the world, and while more research is needed, our study shows that certain cells and pathways are disrupted in endometriosis and may be possible targets for diagnosis and therapy in the future,” he concluded.
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