Human thyroid organoids: tools for understanding thyroid diseases and development

The thyroid gland develops in five main stages, each characterized by specific molecular and cellular processes that are highly conserved across invertebrates and vertebrate species. In vivo studies have elucidated the key molecular players orchestrating each stage of thyroid organogenesis and thyroid hormone biosynthesis, laying the groundwork for developing thyroid organoids in vitro. Thyroid organoids have been successfully derived from mouse and human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, as well as from fetal and adult thyroid tissues. Protocols using directed differentiation through chemical signalling modulators and/or by overexpression of pivotal thyroid transcription factors have yielded thyroid progenitors with varying levels of maturation, differing in timeline, purity and functional outcomes. However, only a few protocols have succeeded in producing thyroid organoids capable of recapitulating thyroid functionality both in vitro and in vivo. This Review explores the various thyroid organoid models currently available, their contributions to understanding thyroid developmental biology and their application in modelling thyroid diseases. We also discuss the current challenges to translating thyroid organoid technology from experimental frameworks into clinical applications, framing the question: could thyroid organoids offer a therapeutic avenue for hypothyroidism, particularly in cases of congenital, post-surgical and treatment-refractory conditions?