Impact of tissue morphology on pluripotent stem cell identity and fate

Title Impact of tissue morphology on pluripotent stem cell identity and fate
Start date 2022-06-20
End date 2027-06-19
Sponsor Horizon Europe Framework Programme
Institution MRC Laboratory of Molecular Biology

Associated cell lines

Project Description

Mammals develop from a small group of pluripotent stem cells that have the task to generate all the cell types and tissue shapes of the organism in an organised manner. How they achieve this is an important and unsolved problem in biology. Most studies of mammalian development have focused on identifying changes in gene expression that guide tissue morphogenesis. However, recent evidence indicates that changes in tissue shape impinge on gene regulatory networks to affect cell fate. This additional yet elusive layer of fate control allows cells to adapt to their dynamic environment. The link between tissue shape and cell fate is particularly relevant at implantation, when the embryo undergoes a dramatic reorganisation as it comes into physical contact with the uterus. This is a critical period in mammalian development associated with changes in gene expression, cell organisation, and overall embryo patterning and morphology, but is poorly understood due to the inaccessibility of the embryo. To overcome this limitation, we recently established embryo culture methods and 3D stem cell models that faithfully recapitulate development at implantation. We aim to dissect how changes in cell identity, cell organisation, and tissue shape are coordinated in mouse and human embryos to ensure the formation of the body plan. Employing state-of-the-art transcriptomics, proteomics, imaging and functional in vivo experiments, we will determine how the organisation of pluripotent stem cells into an epithelial tissue at implantation affects their identity and subsequent specification into distinct cell types. Capitalising on our unique embryo and stem cell cultures that recapitulate the shape-fate crosstalk at implantation, this project is uniquely well-poised to yield an integrated mechanistic understanding of normal embryo development, a first fundamental step in identifying the causes of developmental failure, congenital abnormalities and infertility.