The Society for the Study of Reproduction’s 52nd Annual Conference was held from 18 – 21 July 2019 in San Jose, United States. The theme of the conference was ‘Beyond Possible: Remarkable Transformation of Reproductive Biology’.

Immune cells derailed

Immune cells are responsible for regulating the health of tissues in our bodies and maintaining their ‘normal’ function as well as fighting infection. In women with endometriosis, a number of immune cells have been shown to be dysregulated. Dysregulation of immune cells in the peritoneal cavity, such as macrophages and NK cells, is thought to lead to an environment where ectopic endometrial tissue is able to escape immune clearance and form lesions. A number of talks and posters at SSR focused on immune cell populations in endometriosis, highlighting a vast research effort within the endometriosis field to further understand this aspect of disease.

Júlia Vallvé Juanico, from Professor Linda Giudice’s lab, presented a poster which investigated macrophages in the endometrium of endometriosis patients. Macrophages are immune cells which are intricately involved in endometriosis pathophysiology, stimulating the growth of lesions in the peritoneal cavity as well as the development of new blood vessels and nerves within lesion tissue (1,2). This fascinating research demonstrated that endometrial macrophages from women with endometriosis had an aberrant RNA signature, suggesting that they are dysregulated compared to endometrial macrophages from healthy women.

Whether endometrial macrophage dysregulation could pre-dispose women to development of lesions or whether this could be a consequence of disease is unclear. Further research is therefore required to understand how endometrial macrophages could be involved in endometriosis. This research has the potential to impact on our understanding of endometriosis aetiology, an important research area required to inform the development of new therapeutics.

Chloe Hogg was invited to give an oral presentation in this session summarising findings from her PhD project, which focussed on macrophages in endometriosis. Her talk focussed on characterising the ontogeny and transcriptomic heterogeneity of lesion resident macrophages.

Essentially, where do disease-associated macrophages come from, and are there multiple ‘types’ of macrophages within lesions with a different genetic signature?

Chloe Hogg demonstrated that multiple macrophage populations exist within endometriosis lesions with differential origins and transcriptomic profiles. Understanding which macrophage populations are involved in pathology is an important step before macrophage-targeted treatments may be a possibility for women with endometriosis.

Dr Kanako Hayashi from Southern Illinois University delivered an elegant talk on the effect niclosamide on the intra-abdominal inflammatory environment in endometriosis in the Edinburgh pre-clinical mouse model of endometriosis.

Niclosamide is a drug typically used to treat tapeworm infections; the re-purposing of drugs is an important area to investigate in endometriosis as this offers an accelerated mechanism for increasing the number of treatments available to patients which have already achieved FDA approval. Pre-clinical testing in endometriosis models is therefore an important research area to demonstrate efficacy of drugs already routinely used in the clinic.

With the progression of immunotherapy for diseases, such as cancer, immune cell-targeted therapies offer an attractive avenue for women with endometriosis, negating the requirement for hormonal disruption and offering the potential for specific, cell- targeted treatments. Basic research in this field is a crucial step towards this aim and this year the SSR annual conference showcased a number of projects at the forefront of this research effort.

Bacteria as a potential novel diagnostic tool

Humans are colonised by bacteria within different tissues which are key to maintaining our health, referred to as our ‘microbiota’. Perturbations in the microbiota have been associated with a number of diseases and interest in this field of research has grown within recent years. The endometrium has its own microbiota (3) which is thought to be important for maintaining endometrial health. Women with endometriosis have been shown to possess changes in the bacteria which colonise the vagina and cervix compared to healthy controls (4). The mechanisms behind these changes are currently unknown and whether these changes contribute to development of disease or could potentially exacerbate disease is speculative.

Professor Warren Fosters’s group from McMaster University carried out a similar study looking at bacteria in the endometrium. In their talk, delivered by Jocelyn Wessels, they investigated the microbiome (the genome of the bacteria) in the endometrium of patients with endometriosis and healthy women.

They identified that women with endometriosis had a more diverse and differential microbiota compared to women without disease. They hypothesised that these alterations were at least partially attributed to the inflammatory environment induced by the presence of endometriosis lesions.

This work has the potential to provide a novel diagnostic tool for women with endometriosis which is less invasive than laparoscopic surgery, traditionally used to provide a diagnosis, although the research group emphasises that this was preliminary data and further research is required.

Endometriosis and pregnancy success: a story of fibroblasts

Linda Giudice delivered a fantastic talk on the role of fibroblasts in endometriosis and pregnancy success. Endometriosis is associated with reduced fertility and a number of adverse pregnancy outcomes such as preterm birth and pre-eclampsia (5,6). The mechanisms behind reduced fertility in women with endometriosis, however, are largely unknown and current therapies available, for example in vitro fertilisation (IVF), increase the likelihood of pregnancy but do not treat any underlying pathology. Improved understanding of the mechanisms, which regulate infertility in women with endometriosis, is therefore an important area of research to improve patient outcomes.

Professor Giudice explained that in the endometrium, endometrial stromal fibroblasts are ‘master regulators’ of a number of processes. The endometrium is a dynamic tissue which responds to progesterone by triggering differentiation of cells in a process called decidualisation.

Endometrial stromal fibroblasts are key to this process and respond to progesterone by differentiating into mature cells capable of supporting blastocyst implantation and development (7). Efficient decidualisation of the endometrium is critically required for preparation of the endometrium for implantation and subsequent pregnancy success.

Professor Giudice explained that in women with endometriosis, endometrial stromal fibroblasts have an impaired response to progesterone, so called ‘progesterone resistance’. This progesterone resistance leads to impaired decidualisation and is thought to impact on pregnancy success and outcomes in endometriosis patients (8). Professor Giudice’s group also isolated endometrial stromal fibroblasts from women with endometriosis and demonstrated that they had a more pro-inflammatory genetic profile than those from healthy women – another factor which may stimulate an environment sub-optimal for implantation and embryo survival (9).

Overall, this pioneering work demonstrated that endometrial fibroblast dysregulation in endometriosis patients could impact on a number of pregnancy-related outcomes. The work sheds light on a research area with currently limited knowledge and suggests that targeting of the fibroblast-progesterone signalling pathway may provide clinical benefit for women with endometriosis.

Summary

The talks at SSR2019 exemplified the fantastic research currently being carried out in the endometriosis field. Take away messages included the importance of basic research which aims at understanding dysregulation of key cell types involved in disease. A number of talks and posters also highlighted the importance of drug re-purposing and this has the potential to accelerate the improvement of treatments available to women. Collaboration between scientists/clinicians/pharmaceutical companies is critical for the translation of basic research into treatments for endometriosis patients.

References

Bacci M, Capobianco A, Monno A, Cottone L, Di Puppo F, Camisa B et al. Macrophages are alternatively activated in patients with endometriosis and required for growth and vascularization of lesions in a mouse model of disease. American Journal of Pathology 2009; 175(2): 547–556 Greaves E, Temp J, Esnal-Zufiurre A, Mechsner S, Horne AW, Saunders PTK. Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis. American Journal of Pathology 2015; 185 (8): 2286-2297 Greaves E, Cousins FL, Murray A, Esnal-Zufiaurre A, Fassbender A, Horne AW et al. A novel mouse model of endometriosis mimics human phenotype and reveals insights into the inflammatory contribution of shed endometrium. American Journal of Pathology 2014; 184(7): 1930–1939 Kyono K, Hashimoto T, Nagai Y, Sakuraba Y. Analysis of endometrial microbiota by 16S ribosomal RNA gene sequencing among infertile patients: a single-center pilot study. Reproductive Medicine and Biology 2018;17(3): 297-306 Ata B, Yildiz S, Turkgeldi E, Brocal VP, Dinleyici EC, Moya A, et al. The Endobiota Study: Comparison of Vaginal, Cervical and Gut Microbiota Between Women with Stage 3/4 Endometriosis and Healthy Controls. Scientific Reports 2019; 9(1): 2204 Brosens I. Endometriosis and the outcome of in vitro fertilization. Fertil Steril 2004; 81(5): 1198-1200 Meuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D’Hooge T. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertility and Sterility 2009; 92(1): 68-74 Hess AP, Nayak NR, Giudice LC. Oviduct and endometrium: Cyclic changes in the primate oviduct and endometrium. Knobil and Neill’s Physiology of Reproduction 2006; 337-381 Klemmt PAB, Carver JG, Kennedy SH, Koninckx PR, Mardon HJ. Stromal cells from endometriotic lesions and endometrium from women with endometriosis have reduced decidualization capacity. Fertility and Sterility 2006; 85(3): 564-572 Barragan F, Irwin JC, Balayan S, Erikson DW, Chen JC, Houshdaran S, et al. Human Endometrial Fibroblasts Derived from Mesenchymal Progenitors Inherit Progesterone Resistance and Acquire an Inflammatory Phenotype in the Endometrial Niche in Endometriosis. Biology of Reproduction 2016; 94(5): 118-120

About the author

Chloe Hogg is a 3rd year PhD student from the University of Edinburgh, United Kingdom, working with Dr Erin Greaves (University of Warwick), Professor Andrew Horne, and Professor Jeff Pollard in the MRC Centre for Reproductive Health. Chloe’s PhD research looks at the role of macrophages in endometriosis. In inflammatory disorders such as endometriosis, macrophages (immune cells which usually maintain the health of our tissues) can become dysregulated and support the growth of pathological tissue, contributing to disease. Her research has shed light on the biology of pathology-associated macrophages in endometriosis, contributing to understanding of this perplexing disorder with currently limited treatments.

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