Exploring endometrial cellular heterogeneity and its role in endometriosis using single-cell transcriptomics

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Endometrium is the inner mucosal lining of the uterus that undergoes cycles of regeneration during a female's reproductive years. It has a heterogeneous architecture, comprising of epithelial cells, stromal fibroblasts, vascular smooth muscle cells, endothelial cells, as well as immune, blood cells, and stem/progenitor cells.In around 10% of women of child bearing age, cells resembling the endometrium are found outside of the uterine cavity. This condition is called endometriosis and is characterised as an oestrogen dependent, chronic inflammatory disease. Endometriosis causes subfertility, debilitating chronic and cyclical pain and is estimated to cost the UK economy £8.2 billion a year in healthcare and loss of work. The lack of reliable diagnostic tools as well as disease treatment is caused by poor understanding of the pathogenesis of endometriosis. A recent GWAS study led by Prof. Zondervan identified variants that increase the risk of developing endometriosis; however, the contribution of these factors to disease development is still unclear. Recently, stem cells have also been found to play a role in endometriosis, but their exact function in endometriosis is still unknown.In order to decipher the role of different cell types in normal endometrial functioning as well as endometriosis pathogenesis, the endometrium has to be studied at the single cell level. Conventional 'Bulk' RNA sequencing processes hundreds of thousands of cells at a time, yielding an average value from all cells analysed. This masks the unique character of individual cells, preventing their discovery and understanding of their function and role in tissue physiology. Single-cell RNA sequencing allows the study of hundreds to thousands of cells individually, thereby overcoming tissue heterogeneity. Single-cell gene expression profiling is a novel method, available in Oxford and will be utilised in the proposed study. The study will build on a recent pilot study by Dr Hellner on endometrial single cell RNA sequencing of the endometrium. The project aims to use this cutting-edge technology to study the human endometrium in both normal and disease endometrium, generating the first, comprehensive transcriptome profile of individual endometrial cells.The proposed study aims to:i. Investigate cellular heterogeneity of both healthy and diseased endometrium and to explore distinct populations of cells and their role in endometrial biology through single cell transcriptomics.ii. Identify rare cell populations, such as endometrial stem cells and stromal immune cells within the normal endometrium and endometriotic tissue, that may play a role in disease pathogenesis, by single cell molecular profiling.The project is expected to yield substantial amount of new knowledge in the field of endometrial biology and endometriosis. For the first time, transcriptome profiles of both healthy endometrium and endometriosis tissue will be obtained and provide crucial insight into endometrial biology, which is currently sparse. The differential profiles will enable us to improve classification of the disease as well as facilitate future discovery of specific biomarkers and therapeutic targets for endometriosis. In the long term this will lead to improved patient care.