Defining the transcriptomic programs of transplantable regenerative thyroid progenitors derived from human pluripotent stem cells.

While much of the attention of cell-based therapy in Endocrinology has been focused on the creation of beta-cells for the treatment of type 1 diabetes the development of stem cell technology has allowed for opportunities in many other different areas (f.e. hepatology, pneumology and urology). Normal thyroid development is critical for human development. Congenital hypothyroidism affects 1/4000 births with the vast majority still having no defined cause. This is due in part to a lack of knowledge of the mechanisms regulating early thyroid embryonic development.The secretion of thyroid hormones from the thyroid glands is also essential for neurologic development during childhood and normal metabolic function in adults. Despite the availability of synthetic thyroid hormones for therapeutic use, much remains to be learned about thyroid development and why individuals establish their own set point. Indeed, many patients with hypothyroidism do not feel well on replacement doses of thyroid hormones suggesting that better individualized therapy is needed. Thus, the development of cell-based models of thyroid replacement would greatly facilitate the treatment of thyroid diseases and our understanding of the causes of congenital hypothyroidism. To completely understand the embryonal thyroid lineage development that allow to future cell-based therapies the proposed mentors of this application, Profs Kotton and Hollenberg, have used mouse embryonic stem cells or induced pluripotent stem cells (iPSCs) to engineer an in vitro model system that recapitulates the sequence of thyroid follicular cell development through the selection of Nkx2.1 positive cells. Firstly, this system has allowed them to explore differences in Nkx2.1 positive cells that do not express Pax8 and develop into lung. Secondly they also studied the cells that express both transcriptoric factors and become thyroid follicular cells with full in vivo functional capacity after transplantation .In past publications for example, this model system has revealed the absolute requirement for combinatorial signaling by Bone Morphogenetic Protein and Fibroblast Growth Factor to allow for follicular cell development in multiple model systems, both in vitro and in vivo in xenopus and murine thyroid development . Finally, thanks to these results, we have now the capacity to leverage this system to gain mechanistic insight into follicular cell maturation and regeneration using human iPSCs and to develop functioning thyroid tissue from iPSCs that has the potential to become clinically applicable in the near future. The goal of this grant is to leverage the previously used system to gain mechanistic insight into follicular cell development and develop a more sophisticated system to efficiently create pure populations of human follicular cells from human iPSCs.According with our goals, we will profile the kinetics of the entire transcriptomic program of human thyroid cells over time during their differentiation from primordial pluripotent progenitor stem cells to fully mature functioning follicles to understand the development and function of the thyroid follicular cell . The impact of our research is critical in order to determine the aetiology of congenital hypothyroidism and how somatic mutations cause diseases such as nodular disease and thyroid cancer and, moreover, to begin to develop novel cellular therapies . This would enable new therapeutic approaches based on cell autologous transplantation of engineered cells able to restore normal thyroid hormone secretion in patients affected by congenital or post-surgical hypothyroidism