Endocrine Abstracts

Organoids are tiny, self-organized three-dimensional versions of an organ that are produced in vitro. Human organoids offer unique opportunities to model the development, physiology, and diseases of human tissues while complementing animal models and reducing the need for animal testing. In the thyroid field, there is a lack of a functional human in vitro thyroid model which allows to further explore various aspects related to thyroid development and disease. Thus, the ability to generate TH-producing human follicles from embryonic stem cells would open new perspectives for the human thyroid research field. Here, by transient overexpression of thyroid transcription factors, NKX2-1 and PAX8, in human embryonic stem cells (hESCs), followed by time-dependent treatment with cAMP, hrTSH, Dexamethasone and TGF-beta inhibitor, we aimed to recapitulate thyroid developmental stages and generate the first in vitro functional thyroid derived from human ESC. Stepwise transcriptomics and histological analysis evidenced that the generated protocol recapitulates the gland developmental steps, cell expansion and follicular organization, and finally results in T4 production. In addition, these in vitro-grown follicles were able to maintain histological organization, promote vascular formation, and synthesize and release THs after three weeks of transplantation into the renal capsule of hypothyroid mice. This model opens a new window to better understand thyroid development processes as well as mechanisms/variants causing congenital hypothyroidism. Also, it can be considered as screening tool to test the toxic effects of compounds, in particular endocrine disruptors. Finally, although this model still needs improvement to be therapeutically applicable, it provides a proof-of-concept that generating autologous human thyroid tissue to maintain TH levels is within reach.