Decoding hypoblast development using stem cell models

Early pregnancy loss is common and most often occurs in the first trimester. Ethical and technical limitations mean that we do not understand the mechanics of how the early embryo develops in this period, and therefore cannot fully understand what goes wrong. Consequently, we must build accessible and reliable cellular models to interrogate and reveal processes underpinning embryo development. Following fertilisation, a zygote undergoes continuous cell divisions to form a structure called the blastocyst that contains three founding lineages: epiblast, trophectoderm, and hypoblast. After implantation into the uterus, the epiblast will develop to make the embryo, whilst the trophectoderm and hypoblast makes extra-embryonic tissues that support embryo growth. Our focus in this project is to understand the development and specialisation of the hypoblast, which plays a key role in patterning and providing nutrition to the growing embryo. Indeed, a recent study has shown that blastocysts with fewer hypoblast cells are more likely to fail in later development leading to unsuccessful pregnancies. Recently, we developed an approach that allows us to derive hypoblast cells from human naïve pluripotent stem cells. This method offers a unique opportunity to study how the hypoblast forms, develops, and functions. Building on this, the project will focus on three main objectives: Uncovering the signals that control hypoblast development: We will study how different signals influence the formation of hypoblast cells. By fine-tuning these signals, we aim to create simple, reliable cellular models that accurately represent hypoblast development. Tracing the origins of hypoblast-derived cells: Using a genetic cell-tracing technology, we will investigate how and when various hypoblast-derived cells are formed. Discovering genetic regulatory mechanisms that control hypoblast differentiation: Combining computational predictions and experimental gene perturbations, we will identify the key genetic regulators that ensure precise control of the developmental process. This project uses novel stem cell-based models to address fundamental biological questions and aligns with the "MRC highlight for engineering biology." This research will advance our understanding of hypoblast development and provide novel tools for studies of human embryology. Additionally, the findings could improve the way human embryos are cultured in the lab, with important implications for in vitro fertilisation (IVF) and the understanding of pregnancy failures. Ultimately, the insights gained may lead to better treatments for early pregnancy issues, supporting more successful outcomes for assisted pregnancies.