Wnt signalling; Symmetry breaking mechanism; Pattern formation; Image-based screens; System Biology; Intestinal organoids; Environment sensing mechanism; Cell-to-cell variability; Single-cell approaches
Yang Qiutan, Xue Shi-Lei, Chan Chii Jou, Rempfler Markus, Vischi Dario, Gutierrez Francisca Mauer, Hiiragi Takashi, Hannezo Edouard, Liberali Prisca (2020), Cell fate coordinates mechano-osmotic forces in intestinal crypt morphogenesis, in BioRxiv
Yang Qiutan, Oost Koen C., Liberali Prisca (2020), Engineering human knock-in organoids, in Nature Cell Biology
Mayr Urs, Serra Denise, Liberali Prisca (2019), Exploring single cells in space and time during tissue development, homeostasis and regeneration, in Development
(2019), From single cells to tissue self‐organization, in FEBS Journal
(2019), Self-organization and symmetry breaking in intestinal organoid development, in Nature
A model system of intestinal organoid structures in vitro, which recapitulates most of the processes of morphogenesis and patterning observed in intestinal tissue, is used to understand self-organization and the symmetry-breaking events during collective cell behavior. The symmetry-breaking event can be observed when, despite all single cells in a growing organoid are exposed to a uniform growth-promoting environment, only a fraction of cells acquires specific cell fates, generating asymmetric structures such as crypts and villi. To understand this process in a quantitative and unbiased manner, we developed advanced single-cell imaging and image analysis of intestinal stem cells in 3D organoid development, as well as a novel approach for mapping genetic interactions. For this project prolongation, we will follow-up on our identified network of functional genetic interactions in organoid formation, by analyzing the role of a Retinoic Acid gradient, generated by enterocytes that act anti-parallel to the Wnt gradient generated by Paneth cells, to maintain the spatial organization of differentiated cells during tissue regeneration in intestinal crypts. We will then address the most challenging aspect of cell-to-cell variability: how to perturb it and study causal effects. In order to perturb different subpopulations of cells in intestinal organoid development with spatial and temporal resolution, we will first characterize cis-regulatory regions required for intestinal stem cell differentiation to then use them to specifically visualize and perturb subpopulations and cell-to-cell variability. Finally, we will explore new avenues by using the experimental and computational framework developed in the past three years in intestinal organoids to reveal the determinants of self-organization and symmetry breaking in neurogenesis with neuro-rosettes, neuro-cysts, and brain organoids. This project extension will consolidate the previous project and open new prospects on how single cells exposed to a uniform growth-promoting environment have the intrinsic ability to generate emergent, self-organized behavior resulting in the formation of complex multicellular asymmetric structures such as intestinal and brain organoids.