How science is unravelling the unknowns of the ‘enigmatic’ endometrium

Published 17 May 2021

A well attended Campus meeting in April considered how advances in 3D imaging, uterine immunology, the microbial environment and signalling pathways are adding step by step to our understanding of the pathogenesis of endometrial disorders.

The pathogenesis of disorders of the endometrium – including endometriosis, implantation failure and recurrent miscarriage - is still poorly understood. And sessions at this well attended Campus meeting in April thus reviewed the controversies and knowledge gaps that persist around the influence of stem cells, the immune system, signalling pathways and microbiome on the health of this highly dynamic but complex tissue. What emerged from the two-day virtual event is that mouse models, 3D reconstruction and international projects to map the human uterus are helping to shed new light and identify new therapeutic candidates for treatment.

In the opening lecture, Carlos Simon presented details of the international HUTER (Human Uterus Cell Atlas) project of which he is co-ordinator and which is the first to focus on the transcriptomic, genomic and spatial changes of the uterus at the single cell level throughout the menstrual cycle and across the lifespan. Launched in 2020, HUTER has already identified six major endometrial cell types and four major phases of endometrial transformation.(1) The overall idea is, said Simon, that a comprehensive reference map of the molecular state of cells in all healthy human tissues would encourage the systematic study of physiological states, developmental trajectories and interactions of cells, and provide a framework for understanding cellular dysregulation in human disease.

Dharanai Hapangama outlined work with colleagues at Liverpool Women’s hospital, UK, using 3D reconstruction of the uterus to advance understanding of the role of epithelial progenitor cells in regeneration and disease. He described a just-published study from Japan suggesting that the structure of the glandular epithelium as seen from 3D imaging is different from what has been previously understood by fundamental morphology, and thus potentially paving the way for new therapies.(2)

Epithelial to mesenchymal transition (EMT) is associated with the development of endometrial lesions and Martin Gotte from Munster University Hospital in Germany outlined studies in mouse models suggesting that EMT markers are dysregulated in endometriosis. This triggers invasive growth which is linked to estrogen, non-coding RNAs and other factors including hypoxia; Gotte’s research, included in a recent review in Human Reproduction Update, has shown promising preclinical results for natural-based therapeutics to target EMT.(3)

Are immune cells also a potential target in endometriosis? Erin Greaves said prevention is a challenge because ‘we don’t even know where the disease starts’. Nonetheless, very early work has been initiated using nanoparticles to target macrophages in mouse models in order to understand different gene expressions. Macrophages are central to the pathophysiology of endometriosis, said Greaves from the University of Warwick, UK, but remain underexplored. She and colleagues have developed a mouse ‘menses’ model to analyse the role of macrophages during vascularisation, innovation and pain sensitisation, which has already suggested that monocyte-derived large peritoneal macrophages are seemingly protective whereas endometrial macrophages promote lesion growth.(4) Other questions relating to the immunology of the endometrium which science has thus far failed to address might be answered using human uterine tissue-derived 3D epithelial organoids: these are currently being used to establish how uterine NK cells regulate placentation.

Sam Schoenmakers gave an update on the latest developments in understanding the endometrial microbiome in a talk described by SIG Endometriosis & Endometrium co-ordinator Andrea Romano as ‘provocative and very critical’. Endometrial dysbiosis is associated with pregnancy loss and implantation failure, and Schoenmakers said the role of the microbiome remains a promising field but one with many pitfalls and limitations. One study, from the group of Carlos Simon in Valencia, has found that, while the existence of a stable endometrial microbial environment is associated with the acquisition of endometrial receptivity, pathological modification of this profile is associated with poor reproductive outcomes.(5) The message from Schoenmakers is that contamination of samples and other biases must be overcome, that current focus should be on the role of microbes and development of clinical applications, and that attention should be paid to how to manipulate the microbiome.

In his presentation on cell-signalling, Douglas Gibson said a tight balance was crucial between pro and anti-inflammatory cytokines and chemokines in controlling the menstrual cycle. However, pinning down biomarkers in this area is difficult because they may differ in each menstrual cycle and in every woman. Gibson, from the University of Edinburgh’s Centre for Inflammation Research, showed that mouse modelling has increased understanding of immune cell phenotype and function. Study findings, he said, include immune dysregulation in the peritoneal cavity and in endometrial tissues as factors in the pathogenesis of endometriosis, and that profiling of peritoneal fluid provides insight into inflammatory changes associated with the disease’s diagnosis, stage and symptoms. He added that future therapeutic targets could be identified through greater understanding of the association between peritoneal macrophages and pelvic pain.

Indeed, pain is a primary feature for many women with endometriosis, and Jacek Malejczyk from the Medical University of Warsaw said this was linked with neuroangiogenesis but original studies are still needed to understand the precise mechanism. In endometriosis, vascular endothelial growth factor (VEGF) has been associated with ghrelin, and a study by Malejczyk and colleagues has shown increased VEGF and ghrelin expression in the endometrium of women with recurrent miscarriage, but the role of VEGF in the progression of endometriosis and recurrent miscarriage is unknown.(6)

In words used by Carlos Simon, the endometrium remains an ‘enigmatic’ organ that needs to be understood better. With this in mind, Andrea Romano closed the Campus by urging the 180 participants to use the resources available such as HUTER to test hypotheses to ensure that ‘we don’t have to reinvent the wheel every time’.

1. See
2. Yamaguchi M, Yoshihara K, Suda K, et al. Three-dimensional understanding of the morphological complexity of the human uterine endometrium. iScience 2021;
3. Meresman G, Gotte M, Laschke M. Plants as source of new therapies for endometriosis: a review of preclinical and clinical studies. Human Reprod Update 2021; 27; 367–392. doi:10.1093/humupd/dmaa039
4. Hogg C, Panir K, Dhami P, et al. Macrophages inhibit and enhance endometriosis depending on their origin. Proc Natl Acad Sci 2021; e2013776118. doi:10.1073/pnas.2013776118.
5. Moreno I, Codoner F, Vilella F, et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. AJOG 2016; 215: 684-703.
6. Zwierzchowska A, Iwan A, Hyc A, et al. Recurrent miscarriage is associated with increased ghrelin mRNA expression in the endometrium - a case-control study. Reprod Biol 2018; 18: 12-17. doi:10.1016/j.repbio.2017.11.003

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