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(MRC DTP) Building the human endometrium in vitro: The role of macrophages in receptive and decidual endometrium to optimise reproductive health


Faculty of Biology, Medicine and Health

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Dr E Mann , Prof John Aplin , Dr Peter Ruane , Dr Lamiya Mohiyiddeen No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

The human endometrium is a highly dynamic tissue that rapidly generates over ~20 days and differentiates to form a uterus lining receptive to embryo implantation, further transforming into decidua to support embryonic development, or breaking down before regenerating a few days later. Exquisite coordination between local structural (glandular and stromal), vascular and immune cells is required to perform these feats under hormone control. Dysfunctional endometrium can lead to infertility, pregnancy complications, and serious benign and malignant diseases. Together, these pathologies affect a significant fraction of women and families, and pregnancy complications negatively impact the lifelong health of offspring. Although uterine natural killer cells have been characterised in depth, other immune cells in the uterus including macrophages are poorly defined despite their critical role in tissue repair and regeneration. Furthermore, dysregulated macrophage function directly drives chronic inflammation causing abnormal tissue structure in other tissues1.

The Maternal and Fetal Health Research Group are specialised in endometrial organoid culture2; the recapitulation of 3D endometrial glands in vitro from primary tissue, which mimic cellular changes seen during the menstrual cycle in response to endocrine and pregnancy hormones. In this project, we will utilise mucosal immunology expertise within the Lydia Becker Institute to combine endometrial organoid culture with immune cells, dissecting immune cell interactions in models of proliferative, receptive and decidual endometrium for the first time. Complex organoid cultures will be assembled from human endometrial tissue, combined with distinct immune cell populations including macrophages and other cells involved in immune tolerance including T cells and dendritic cells. Optimisation of complex organoid culture and characterisation of the interactions between cell populations will be based on gene expression and immunological analysis in isolated populations. These interactions will be monitored in response to estrogen (proliferative), progesterone (receptive), and placental hormones (decidual).

The establishment of complex endometrial organoids will also enable investigation of interventions for endometrial pathologies. Intrauterine treatment with placental hormone human chorionic gonadotrophin (hCG) at the time of embryo transfer is an intervention in assisted reproductive technologies (ART) that has been shown to greatly improve live birth rates, likely through local action on the receptive endometrium3,. Assaying the effects of hCG in complex organoids will provide mechanistic insight into this emerging treatment.

Building techniques to maintain tissue-like multiple cell-type cultures and providing proof of principle that such systems can interrogate disease and intervention mechanisms is highly relevant to the ART industry and other biotechnology industries.

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships



Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/

References

1. Wynn TA, Barron L. (2010). Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis. 30(3):245-57.

2. Craciunas L, Tsampras N, Raine-Fenning N, Coomarasamy A. (2018). Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction. Cochrane Database Syst Rev. Oct 20;10:CD011537.

3. Turco MY, Gardner L, Hughes J, Cindrova-Davies T, Gomez MJ, Farrell L, Hollinshead M, Marsh SGE, Brosens JJ, Critchley HO, Simons BD, Hemberger M, Koo BK, Moffett A, Burton GJ (2017). Long-term, hormone responsive organoid cultures of human endometrium in a chemically defined medium. Nat Cell Biol. 19:568-577
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