Decrypting deficient embryo-endometrium interaction in infertility using cutting-edge blastocyst and endometrium models: spotlights on endometriosis and polycystic ovary syndrome

One week after fertilization, the human embryo implants into the uterus, requiring highly coordinated crosstalk with the uterine lining (endometrium). To welcome and nest the nascent embryo (blastocyst), the endometrium must decidualize and reach a receptive state. Perturbed decidualization and receptivity are considered to be major causes of infertility. Here, we will deeply decrypt aberrations in these processes in two widespread burdening diseases highly associated with infertility, i.e. endometriosis and polycystic ovary syndrome (PCOS), to date only poorly understood. We will apply our recently designed unique in vitro human implantation model in which high-fidelity embryo models (blastoids) are combined with biomimetic endometrium constructs, found to reliably capture the first events of embryo-endometrium interaction. The endometrium mimics are developed from organoids established from endometrial biopsies of healthy (fertile) or infertile patients, which typically recapitulate the original tissue characteristics. Using the organoid and implantation models, we will unravel the mechanisms perturbed in endometrial decidualization and embryo interaction in endometriosis and PCOS, by applying cutting-edge single-cell multi-omics, followed by functional validation through pharmacological and CRISPR/Cas9 genetic interference. Our study will provide deep insight into what goes wrong at the embryo-woman interface in the prevalent infertility- associated endometriosis and PCOS.