17 December

Thyroid organoids: measuring hormonal changes in a dish

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Researchers from the lab of Hans Clevers (Hubrecht Institute) – in collaboration with the UMC Utrecht, the Utrecht Platform of Organoid Technology (UPORT) and Maastricht University – used organoid technology to grow miniature human thyroids that produce thyroid hormones. These mini-thyroids can be used to model how thyroid hormones are produced and how this is regulated in health and disease. Scientists worldwide can use the model to identify new treatment options for patients suffering from thyroid diseases, like Graves’ disease. The results were published in Proceedings of the National Academy of Sciences (PNAS) on the 13th of December.

 

Image of Thyroid organoids
Thyroid organoids containing a pure population of thyroid follicular cells. Blue = cell nucleus (DAPI), Green = cell membrane (Phalloidin), Red and white = thyroid follicular cell transcription factors (PAX8 and NKX2.1). Credit: Jelte van der Vaart, copyright: Hubrecht Institute.

The thyroid gland is responsible for maintaining a stable metabolism of the human body throughout different seasons and it does so by secretion of thyroid hormones into the blood stream. These hormones are essential for everyday life. Menno Vriens (UMCU), endocrine surgeon and co-author on the project, explains: “Dysfunction of the thyroid gland leads to a wide variety of symptoms due to the diversity of functions of the thyroid hormones. Diseases caused by a misbalance in the secretion of thyroid hormones, called hypo- or hyperthyroidism, emphasize the necessity of tight regulation of hormone production.” However, understanding the exact biology behind the functioning of the human thyroid gland requires a reliable laboratory model. Reason enough for the group of Hans Clevers to develop an organoid-based model for the healthy adult thyroid.

Hormone-producing organoids

Researchers from the Hubrecht Institute used organoid technology to grow miniature versions of the mouse and human thyroid in a dish. These so-called organoids are tiny 3D-structures that mimic the function of actual organs. After achieving expansion of these organoids, the researchers had to make sure the mini-thyroids produced hormones and responded to the right stimuli. Jelte van der Vaart, researcher on the project, explains: “The organoids are grown in a cocktail of factors that stimulate growth but to our surprise we also discovered that the organoids immediately started producing thyroid hormones. When we stimulated the organoids using thyroid stimulating hormone (TSH), this even led to increased hormone production.” The organoids contain the complete machinery of thyroid hormone production but also store premature hormone as back-up on the inside – also called the lumen – of the organoids. “This phenomenon is highly similar to what we see in humans. By storing hormones as finished products, the thyroid can rapidly respond to stimuli,” Van der Vaart says.

Image of thyroid organoid
Thyroid organoids storing thyroid hormones in the lumen. Blue = cell nucleus (DAPI), Green = cell membrane (Phalloidin), Red = thyroid hormone carrier protein (Thyroglobulin). Credit: Jelte van der Vaart, copyright: Hubrecht Institute.
High similarity to thyroid gland

Organoids can be seen as avatars of the human body in a dish. The researchers used state-of-the-art techniques to verify the similarity between an actual human thyroid gland and the thyroid organoids. In collaboration with Maastricht University, they made images at high magnification, which showed that the cells of the organoids recapitulate the characteristics of actual thyroid cells. Moreover, using a technique called single-cell sequencing, they found a large overlap between the cells in thyroid organoids and those from patient tissue. However, a single population of cells stood out. Van der Vaart explains: “While thyroid tissue does not expand through cell division, we found that the organoids do: the organoids contain special cells, which likely represent the thyroid stem cells.” Of note, the research group of Prof Rob Coppes published a very similar study, just a few months ago, and demonstrated transplantability of such thyroid organoids.

Autoimmune disease in a dish

The newly-developed organoids provide a valuable tool for studying fundamental thyroid biology. Additionally, the researchers showed the potential of using the organoids as models for autoimmune thyroid diseases (AITD). The immune system of patients with AITD produces antibodies that either stimulate (Graves’ disease) or decrease (Hashimoto’s disease) thyroid hormone levels. Current treatment uses anti-thyroid drugs, irradiation or resection to cure the disease. These therapeutic interventions cause patients to need lifelong supplementation of thyroid hormones.

Van der Vaart and colleagues incubated thyroid organoids with serum from Graves’ disease patients and observed increased growth and increased hormone secretion, which is similar to what occurs in patients. “Since the organoids recapitulate the symptoms of the disease, we may be able to test new potential therapeutics to cure the disease in these organoids without the need for thyroid tissue removal”, Van der Vaart concludes.

Publication

Adult Mouse and Human Organoids derived from Thyroid Follicular Cells and modelling of Graves’ Hyperthyroidism. Jelte van der Vaart, Lynn Bosmans, Stijn F. Sijbesma, Kèvin Knoops, Willine J. van de Wetering, Henny G. Otten, Harry Begthel, Inne H.M. Borel Rinkes, Jeroen Korving, Eef G.W.M. Lentjes, Carmen Lopez-Iglesias, Peter J. Peters, Hanneke M. van Santen, Menno R. Vriens, Hans Clevers. PNAS, 2021.

 

 

Hans Clevers is group leader at the Hubrecht Institute for Developmental Biology and Stem Cell Research and at the Princess Máxima Center for Pediatric Oncology.