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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


Project Description

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:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

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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