How does epithelial tissue organization modulate pluripotent stem cell identity and fate?
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During embryogenesis pluripotent stem cells give rise to all the cell types present in the organism. How pluripotent cells decide their fate is a fundamental question in development and regeneration. This question has been mainly addressed in the context of 2D culture platforms that do not recapitulate the organization of the tissues in the embryo. Therefore, the aim of this project is to understand how tissue organization modulates pluripotent stem cell identity and fate.
The project will focus on the early post-implantation period of mouse embryo development, as this is the stage at which cells lose their pluripotent character and commit to a specific lineage. Prior to pluripotency exit, cells are organized into an epithelial tissue that surrounds a luminal cavity. The central hypothesis of this work is that epithelial tissue organization modulates pluripotent stem cell identity and fate. We have recently developed a novel methodology to culture pluripotent stem cells in 3D as epithelial spheroids, which allows us to model the organization of the early post-implantation embryonic tissue. Using this culture system we will explore the potential role of the lumen as a modulator of stem cell identity. The main objectives are: (i) to identify luminal signals, (ii) to disrupt epithelial and luminal integrity, and assess the effects on stem cell identity, (iii) to determine the molecular mechanisms, and (iv) to validate the findings in in vivo developing mouse embryos. This will entail a combination of methodologies including proteomics, generation of knockout and transgenic embryonic stem cell models, and embryo-embryonic stem cell chimera experiments.
The results from this project will help us to dissect the molecular mechanisms that control pluripotent stem cell identity in a physiological 3D context.
Shahbazi MN., Zernicka-Goetz M. (2018)
Deconstructing and reconstructing the mouse and human early embryo.
Nat Cell Biol. 20(8): 878-887.
Shahbazi MN., Scialdone A., Skorupska N., Weberling A., Recher G., Zhu M., Jedrusik A., Devito LG., Noli L., Macaulay IC., Buecker C., Khalaf Y., Ilic D., Voet T., Maironi JC., Zernicka-Goetz M. (2017)
Pluripotent state transitions coordinate morphogenesis in mouse and human embryos.
Nature 552(7684): 239-243.