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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 tissues.
In this project, we will utilise mucosal immunology expertise within the Lydia Becker Institute combined with endometrial organoid culture, which the Maternal and Fetal Health Research Group are extensively specialised in. This project will dissect immune cell interactions in models of proliferative, receptive and decidual endometrium for the first time, to enable characterisation of critical regulators of implantation in early pregnancy. The establishment of complex endometrial organoids will also enable investigation of interventions for endometrial pathologies. Intrauterine treatment with placental hormone human chorionic gonadotropin (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 endometrium. Assaying the effects of hCG in complex organoids will provide mechanistic insight into emerging treatment.

Training/techniques to be provided:
Whole organ phyioslogy – development of multi cell-type 3D cultures from primary tissue to recapitulate in vitro endometrial function using organoid culture system.

Mucosal immunology techniques – processing human mucosal tissue for cellular and molecular characterization of endometrial immune cells (flow cytometry and molecular techniques).

Bioinformatics: characterisation of immune cells using techniques such as single cell RNAseq

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a topic related to biological and medical sciences. Candidates with experience in cell biology, development or immunology or with an interest in reproductive medicine are encouraged to apply.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy 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

Scott, N.A. and Mann, E.R. (2019). Regulation of mononuclear phagocyte function by the microbiota at mucosal sites. Immunology. Accepted for publication.

Scott, N.A., Andrusaite, A., Andersen, P., Lawson, M., Alcon-Giner, C., Leclaire, C., Caim, S., Le Gall, G, Shaw, T., Connolly, J.P.R., Roe, A.J., Wessel, H., Bravo-Blas, A., Thomson, C., Kästele, V., Wang, P., Peterson, D.A., Bancroft, A., Li, X., Grencis, R., Mowat, A.M., Hall, L.J., Travis, M.A., Milling, S.W.F. and Mann, E.R. (2018). Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis. Science Translational Medicine. 10(464)

Kelly, A., Gunalty, S., McEntee, C.P., Shuttleworth, E.E., Smedley, C., Houston, S.A., Fenton, T.M., Levison, S., Mann, E.R. and Travis, M.A. (2018). Human monocytes and macrophages regulate immune tolerance by integrin avb8-mediated TGFb activation. Journal of Experimental Medicine. 215(11):2725-273
PT Ruane, C Buck, PA Babbington, W Aboussahoud, SC Berneau, M Westwood, SJ Kimber, JD Aplin, D R Brison (2019). The effects of hyaluronate-containing medium on human embryo attachment to endometrial epithelial cells in vitro. Human Reproduction Open. In Press
PT Ruane, SC Berneau, R Koeck, J Watts, SJ Kimber, DR Brison, M Westwood, JD Aplin (2017). Apposition to endometrial epithelial cells activates mouse blastocysts for implantation. Molecular Human Reproduction 23:617-627.

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