Adult mouse and human organoids derived from thyroid follicular cells and modeling of Graves' hyperthyroidism

Significance The thyroid is essential for maintaining systemic homeostasis by regulating thyroid hormone concentrations in the bloodstream. This study describes an organoid-based model system to study mouse and human thyroid biology. Moreover, the study explores the potential of human organoids for modeling autoimmune disease, the anti-TSH receptor (TSHR) antibody-driven Graves’ hyperthyroidism.
The thyroid maintains systemic homeostasis by regulating serum thyroid hormone concentrations. Here we report the establishment of three-dimensional (3D) organoids from adult thyroid tissue representing murine and human thyroid follicular cells (TFCs). The TFC organoids (TFCOs) harbor the complete machinery of hormone production as visualized by the presence of colloid in the lumen and by the presence of essential transporters and enzymes in the polarized epithelial cells that surround a central lumen. Both the established murine as human thyroid organoids express canonical thyroid markers PAX8 and NKX2.1, while the thyroid hormone precursor thyroglobulin is expressed at comparable levels to tissue. Single-cell RNA sequencing and transmission electron microscopy confirm that TFCOs phenocopy primary thyroid tissue. Thyroid hormones are readily detectable in conditioned medium of human TFCOs. We show clinically relevant responses (increased proliferation and hormone secretion) of human TFCOs toward a panel of Graves’ disease patient sera, demonstrating that organoids can model human autoimmune disease.