Saracino, Federica (2023) Dissecting the mechanisms underlying symmetry breaking and tissue-scale organization in development and disease. [Tesi di dottorato]

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Abstract

A major and still unresolved question in developmental and stem cell biology is how homogeneous multicellular aggregates of stem cells self-organize into asymmetric structures that closely resemble complex organs and tissues, named organoids. Crucial in this process is the first symmetry breaking event in which a fraction of an apparently uniform aggregate of cells differentiate despite all cells being exposed to a uniform growth-promoting environment. To address this issue, I have used different 2D and 3D stem cell-based in vitro models and interrogated the mechanism(s) that triggers symmetry breaking and cell fate transition using a chemical genetic approach. Small molecules are indeed easy to apply to cells and may often work reversibly, thus offering a valuable and flexible approach to investigate dynamic cellular processes like morphogenesis, complementing the genetic methods. In particular, I have focused my research activity on a glucocorticoid widely used to treat airways and gastrointestinal syndromes including Chron’s disease, named budesonide, and found that it unexpectedly acts as a potent inhibitor of this process in embryo-like organoids (3D gastruloids) and patients-derived colorectal cancer organoids. The mechanism underlying this previously unexplored activity of budesonide was also investigated.

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