A common feature of polarized simple epithelia is their ability to generate and maintain tubular and spheroidal fluid-filled structures, which is essential for embryonic blastocyst formation, gastrulation, neural tube formation, lung development and glandular sprouting. These processes require both strong intercellular adhesion and regulated expansion of the epithelial cell assemblies coupled to luminogenesis resulting in structures with defined mechanobiological properties. Spheroidal organoids have attracted considerable attention in examining tissue morphogenesis with direct applications for tissue engineering28-32. Project area A focuses on the mechanobiology of spheroids to elucidate fundamental epithelial properties. A1 investigates how mechanical cues affect the self-organization and differentiation of embryoid bodies derived from pluripotent stem cells. A2 studies the mechanobiology of mammary-gland-derived spheroids to understand the role of intracellular (cytoskeleton), intercellular (adhesions) and extracellular mechanical cues (ECM) in the context of mammary gland formation, maintenance and breast cancer invasion. A3 uses 3D confrontation assays of endometrial- and trophoblast-derived spheroids to investigate how hormone-dependent mechanical properties affect human embryo implantation and placentation during pregnancy. A4 derives 3D models from existing 2D data and uses the new experimental data to provide a 3D physical description that will help to understand and model the biological phenomena observed in A1 and prompt new experiments and analyses.
Impact: The expected results will identify novel means to guide in vitro tissue differentiation by using mechanical cues (A1). This will contribute to our understanding of how mechanical factors affect tumor cell metastasis (A2) and will help to devise strategies for improved blastocyst implantation after in vitro fertilization and, conversely, for efficient contraception (A3). The proposed coupling between modeling and experimentation is expected to reduce the amount of necessary exploration (A4). On a more basic level, it will highlight the influence of topologies, i.e., give insights into how finite size in one (tubes) or both (spheres) dimensions determines epithelial self-organization and properties.
