Abstract
Euthyroidism is of profound importance for lifetime health. However, the early diagnosis or therapeutics of thyroid developmental defects has not been established, mainly due to limited understanding of human thyroid development and a lack of recapitulating research model. Herein, the authors elaborate the cell atlas and potential regulatory signaling of the evolution of heterogeneous thyrocyte population from 12 to 16 gestational weeks. Moreover, they establish a long-term culture of human fetal thyroid organoids (hFTOs) system, which retains the fetal thyroid lineages and molecular signatures, as well as the ability to generate functional human thyroid follicles post mice renal transplantation. Notably, cAMP signaling activation in hFTOs by forskolin boosts the maturation of follicle and thus thyroid hormone T4 secretion, which recapitulates the key developmental events of fetal thyroid. Employing this ex vivo system, it is found that enhanced chromatin accessibility at thyroid maturation genes (such as TPO and TG) loci permits the transcription for hormone production. This study provides the cell atlas of and an organoid model for human thyroid development, which will facilitate thyroid research and prospective medicine.