Public Thesis Defense of Léolo GONAY

"Mathematical modelling of epithelial growth, fission and lumen formation during embryonic thyroid development : a combination of computational and experimental approaches"

Organogenesis is the phase of embryonic development leading to the formation of fully functional organs. It can be divided into two main processes: morphogenesis (acquisition of a shape and cellular organisation) and differentiation (acquisition of cellular function). The thyroid, a highly vascularised endocrine gland, derives from the endoderm and develops into its typical architecture (a multitude of tightly packed independent spherical follicular units) starting from a 3D mass of epithelial thyroid progenitors. Follicular organisation is unique and essential for thyroid function, i.e. thyroid hormone (T3 and T4) production. Previous in silico studies showed that endothelial cells, besides their nutritive function, play a central role in thyroid gland morphogenesis. However, the precise mechanisms and biological parameters controlling the organisation of the thyroid epithelial progenitors into a multitude of single-layered thyroid follicles remain unknown. Animal experimentation to improve our knowledge of organogenesis is time- and money-consuming and has clear limitations. Here, we developed and used a 2-D vertex model of thyroid growth, angiogenesis and folliculogenesis, within the open-source Chaste framework. Our in silico model, based on initial in vivo images, correctly simulates the differential growth and proliferation of (central and peripheral) epithelial progenitors, as well as the morphogen-driven migration of endothelial cells, consistent with our experimental data. We show that endothelial invasion, associated with changes in epithelial cell adhesion, are key in driving the fission of the 3D epithelial mass into independent pre-follicular units. We also found that endothelial cells abundance and proximity to epithelial cells could induce their polarisation and subsequent opening of a cavity in the centre of the follicle. Our study illustrates how constant dialogue between theoretical and experimental approaches helped us better understand the role of cell migration, adhesion and polarisation in the embryonic development of the thyroid. We anticipate that the use of in silico models such as the one developed here can push forward the fields of developmental, regenerative or even medical biology.