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

Abstract

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.

Modeling Human Thyroid Development by Fetal Tissue‐Derived Organoid Culture

“…[ 11 ] Consistently, the dependence of adult TFC cells on the cAMP pathway has been reported by the latest study on adult mouse and human thyroid organoids. [ 30 ] However, when cAMP initiated in fetal thyroid and when subsequent cascade events occur in the narrow time window from thyroid organogenesis to functional maturation still remain elusive. Our study indicates the significance of cAMP activation during fetal thyroid maturation and demonstrates heterogeneity of fetal thyrocytes in cAMP signal response.…”

Patient-derived parathyroid organoids as tracer and drug-screening application model

“…This is in line with results from a recent study by van der Vaart et al . in thyroid organoids who could not find evidence for the existence of unique thyroid stem cells (26). They described that many solid tissues do not rely on a professional stem cell for their maintenance and repair, but rather temporarily recruit differentiated cells into a transient progenitor pool (26), suggesting that this phenomenon is also applicable to the thyroid or in this case even parathyroid gland.…”

“…When comparing immunolabeling of parathyroid tissue with parathyroid organoids, similarities were seen in the expression pattern of GCM2, CHGA, PTH and CaSR (Figure 4). To study the presence of stem cell markers in human PTOs, we analyzed the most proposed stem cell markers as listed by van der Vaart et al (26), using bulk RNA-sequencing. No upregulation was observed in the putative stem cell markers MKI67, ATXN1, FUT4, REOX1, HHEX, NGFR, TTF2 and SOX2, when comparing PTOs and dPTOs to tissue (Supplemental Figure 6).…”

“…Organoids are 3D structures that closely recapitulate tissue architecture and cellular composition and are developed from stem cells (17). Organoid models have been developed from multiple exocrine and endocrine glandular tissues (18)(19)(20)(21)(22)(23)(24)(25)(26). These models have proven very useful for studying tumor behaviour and assessing drug responses, and have provided a platform for long-term in vitro experimentation (18)(19)(20)(21)(22)(23).…”

Machine learning identifies baseline clinical features that predict early hypothyroidism in patients with Graves’ disease after radioiodine therapy

“…Graves’ disease (GD) is an autoimmune disease with the overproduction of thyroid-stimulating hormones (TSH) induced by the activation of thyrotropin-receptor antibodies (TRAb) ( 1 ). It is the most common cause of hyperthyroidism, which has significant adverse effects on many organ systems, such as cardiovascular, metabolism, growth, and gastrointestinal ( 2 ). Epidemiological studies showed that the incidence of Graves’ hyperthyroidism in the United States is around 20–40 cases per 100,000 individuals per year ( 3 , 4 ).…”