Cell type-specific endometrial dysfunctions across the menstrual cycle and their potential for drug interventions in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) affects 11-13% of reproductive-age women and is one of the leading causes of anovulatory infertility. Women with PCOS have elevated androgen levels, polycystic ovarian morphology, and ovarian dysfunction. The PCOS endometrium is exposed to constant estrogen, which leads to progesterone resistance and impaired decidualization. As a result, PCOS women are twice as likely to have a non-receptive endometrium. This hinders embryo implantation and increases the risk of pregnancy complications, such as miscarriage. However, whether changes in the cellular complexity and heterogeneity of the endometrium during the menstrual cycle contribute to PCOS-specific endometrial dysfunction remains unclear. The overarching aim of this MSCA-PF project is to uncover PCOS and cell type-specific endometrial dysfunction across the menstrual cycle at the single cell level and to test whether the identified markers can serve as targets for future drug development. Using a unique collection of human endometrial biopsies from women with and without PCOS and single nuclei RNA sequencing, I will (1) map the endometrium at the single-cell level at four different menstrual stages, define the composition of cell types and key molecular regulatory networks; (2) establish and characterize 3D mono- and co-culture models of patients endometrium and investigate their ability to mimic tissue of origin; and (3) determine factors that facilitate PCOS-specific epithelial-stroma communication and endometrial response to novel drug treatments. By accomplishing these goals and sharing the transcriptomic data as a PCOS endometrial cell atlas and protocols for patient-derived cell models, the proposed project will provide valuable resources for new discoveries. Ultimately, the project aims to improve the diagnosis, treatment, and prevention of endometrial dysfunction in PCOS. Further, it provides me with a strong training path towards academic independence in Europe.