Fredrik Lanner

Motherhood holds a profound significance for many women, yet one in six couples encounters infertility. In vitro fertilization (IVF), the most common treatment, yields modest pregnancy rate. Moreover, 15% of all pregnancies are spontaneously miscarried. Embryo implantation and pregnancy progression rely on communication between genetically normal, euploid embryo and uterus, complemented by favorable microbiota. Even following the transfer of the tested euploid embryo, a maximum implantation rate of 50% is achieved, causing the need for multiple transfers. The fact that failed implantation and pregnancy loss are common, underscores the importance of hostile endometrial environment, impaired embryo-maternal communication, and dysbiotic uterine microbiota in poor fertility. PODIUM project adopts a holistic approach to unravel the interplay between endometrial, embryonic, and host microbiota factors underlying the etiology of implantation failure and pregnancy loss. We adopt systems biology approach, based on our expertise in conducting integrated multiomic and microbiota profiling of endometrium. This approach will be augmented by using our in vitro implantation models, including embryo-like blastoids and endometrial organoids, to delve into implantation mechanisms. Thus, PODIUM contributes to the clinical field, which is often neglected, and paves the way for enhanced diagnostic abilities and the development of personalized treatments for female poor reproductive outcome.

Understanding fundamental principles that regulate the early human embryo has clinical value for reproductive technologies, congenital disease, and regenerative medicine. My lab and others have begun to uncover the molecular mechanisms controlling the first week of development but following implantation, we have very poor understanding beyond historic histological characterisations. We have learned a lot from the mouse, but human post-implantation development is very distinct from mouse. One example, following implantation a primate specific cell type fills the blastocoel cavity prior to gastrulation, the extra embryonic mesenchyme. This cell type is completely lacking in the mouse.New opportunities to study post-implantation development has emerged through extended blastocyst cultures and stem cell-based embryo models. In this project we will build a comprehensive spatial single cell transcriptional atlas of implantation, describing the cell types and the genes that control them. This resource will be critical to validate blastoids and post-implantation embryo models. Functionally we will use the transcriptional information and validated embryo models, together with genome editing to dissect regulators of the implantation event and lineage specification of the extra embryonic mesenchyme and amnion. Lastly, we will extend our recent studies of the epigenetic control through Polycomb Repressive Complex 2, histone deacetylation and X-chromosome inactivation in female embryos.