Abstract
Organogenesis is the phase of embryonic development leading to the formation of fully functional organs. In the case of the thyroid, organogenesis starts from the endoderm and generates a multitude of closely packed independent spherical follicular units surrounded by a dense network of capillaries. Follicular organisation is unique and essential for thyroid function, i.e. thyroid hormone production. Previous in vivo studies showed that, besides their nutritive function, endothelial cells play a central role during thyroid gland morphogenesis. However, the precise mechanisms and biological parameters controlling the transformation of the multi-layered thyroid epithelial primordium into a multitude of single-layered follicles are mostly unknown. Animal studies used to improve understanding of organogenesis are costly and time-consuming, with recognised 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 in vivo images, correctly simulates the differential growth and proliferation of central and peripheral epithelial cells, as well as the morphogen-driven migration of endothelial cells, consistently with our experimental data. Our simulations further showed that reduced epithelial cell adhesion was critical to allow endothelial invasion and fission of the multi-layered epithelial mass. Finally, our model also allowed epithelial cell polarisation and follicular lumen formation by endothelial cell abundance and proximity. Our study illustrates how constant discussion between theoretical and experimental approaches can help us to better understand the roles of cellular movement, adhesion and polarisation during thyroid embryonic development. We anticipate that the use of in silico models like the one we describe can push forward the fields of developmental biology and regenerative medicine.
Highlights
The thyroid is a highly vascularised endocrine gland responsible for the synthesis of triiodothyronine (T3), thyroxine (T4) and calcitonin
We developed a method to generate more biologically-realistic initial conditions (IC) from microscopic images of the thyroid (Figure 2). This method enables the transformation of any images processed in the image analysis platform HALO into a numerical structure that can be further used in Chaste as initial condition (IC) for our Vertex models (VMs)
We created a bridge between experimental science and mathematical modelling, transforming qualitative and descriptive biological information into quantitative data that can be used to drive a process-based morphogenesis model
Summary
The thyroid is a highly vascularised endocrine gland responsible for the synthesis of triiodothyronine (T3), thyroxine (T4) and calcitonin. The functional unit of the thyroid is called the follicle It is a spherical structure composed of a single layer of epithelial follicular cells, the thyrocytes, resting on a continuous basement membrane and surrounding a central cavity. This cavity, or lumen, contains the colloid, a homogeneous non-crystalline substance consisting of large iodinated molecules of thyroglobulin (Tg) that constitute the thyroid hormone reservoir. The basement membrane that surrounds the follicular cells is a thin, non-cellular matrix that separates the epithelial monolayer from the underlying connective tissue It is mainly composed of collagens, fulfilling a structural role, and laminins, forming cross-shaped and multi-adhesive structures ensuring adhesion with the epithelial surface. These cells are found interspersed between the follicles with which they are closely associated [1,2,3]
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