Master in Biophyics, Biochemistry and Biotechnology- KULeuven 2021
2022-2023, 2023-2024 : Bourse en l’honneur de Sophie et Christian Terlinden
Modeling congenital Hypothyroidsm with human thyroid organoids
The function of the thyroid gland is to capture iodide in order to synthesize hormones
that act on almost all tissues and are essential for normal growth and metabolism1.The aim of the proposed project is to use human thyroid organoids for modeling congenital hypothyroidism with dysgenesis (CHTD) in vitro. We will take advantage of:
1) our expertise in generating functional human thyroid organoids from pluripotent stem cells
2) the availability of IPSc from homozygous twins, discordant for CHTD2.
The goal is to identify the underlying molecular mechanisms ofCHTD by generating thyroid organoids from IPSc. The translation of identified or unidentified genetic/epigenetic abnormalities of patients with CHTD into experimentally validated models of pathogenic mechanisms will be a central paradigm of this project strategy.
The thyroid gland synthesises thyroid hormones, which are involved in the growth, development, and metabolism of almost all tissues. Patients with congenital hypothyroidism lack a functional thyroid gland. A larger subset of these patients has thyroid dysgenesis, i.e. a thyroid gland that has not developed normally. Thyroid dysgenesis is often a sporadic disorder, and the genetic cause is identified in less than 10% of cases. An experimental model using pluripotent stem cells (capable of giving rise to any type of specialised cell) that develop into thyrocytes and then into thyroid follicles would allow us to understand the different stages of thyroid development. Fibroblasts are cells found in the skin. They can be easily cultured from a simple microbiopsy (a fe millimeters of skin) and can be both preserved and propagated. These fibroblasts can then be converted into pluripotent stem cells, which in turn differentiate into cells of various organs (retina, pituitary, heart, lung) that can even organise in vitro to form a structure similar to that of the organ in vivo.
Prof. Costagliola's team (IRIBHM-ULB) has published the method by which pluripotent mouse stem cells, and more recently human stem cells, can be differentiated into functional thyroid follicular structures. The aim of this study is to differentiate into thyroid follicles, fibroblasts from monozygotic twins (i.e. same genetic background) discordant (i.e. one individual is affected, the other is not) for thyroid dysgenesis. If the fibroblasts of the twins behave differently during thyroid morphogenesis, mimicking the initial clinical observation, a comprehensive study of the expression of all gene networks within each lineage is performed to identify the molecular differences that might explain the discordant phenotype. If the fibroblasts behave identically in vitro, this raises the question of environmental causes that might produce the different phenotypes in utero or epigenetic changes that would be neutralised in vitro.
Whatever the outcome, whether or not the discordance is maintained in vitro, this work will contribute to a better understanding of the mechanisms involved in congenital hypothyroidism with dysgenesis.