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

Jelte van der Vaart; Lynn Bosmans; Stijn F. Sijbesma; Kevin 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

doi:10.1073/pnas.2117017118

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

Jelte van der Vaart, Lynn Bosmans, Stijn F. Sijbesma, Kevin 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	2117017118
Number of pages	11
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	118
Issue number	51
DOIs	https://doi.org/10.1073/pnas.2117017118
Publication status	Published - 21 Dec 2021

Keywords

thyroid
organoids
Graves' disease
STEM-CELLS
IN-VITRO
TSH
GENERATION
DIFFERENTIATION
PROLIFERATION
REGENERATION
POPULATION
FOLLICLES
CULTURES

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10.1073/pnas.2117017118Licence: CC BY

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van der Vaart, J., Bosmans, L., Sijbesma, S. F., Knoops, K., van de Wetering, W. J., Otten, H. G., Begthel, H., Rinkes, I. H. M. B., Korving, J., Lentjes, E. G. W. M., Lopez-Iglesias, C., Peters, P. J., van Santen, H. M., Vriens, M. R., & Clevers, H. (2021). Adult mouse and human organoids derived from thyroid follicular cells and modeling of Graves' hyperthyroidism. Proceedings of the National Academy of Sciences of the United States of America, 118(51), Article 2117017118. https://doi.org/10.1073/pnas.2117017118

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title = "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.",

keywords = "thyroid, organoids, Graves' disease, STEM-CELLS, IN-VITRO, TSH, GENERATION, DIFFERENTIATION, PROLIFERATION, REGENERATION, POPULATION, FOLLICLES, CULTURES",

author = "{van der Vaart}, Jelte and Lynn Bosmans and Sijbesma, {Stijn F.} and Kevin Knoops and {van de Wetering}, {Willine J.} and Otten, {Henny G.} and Harry Begthel and Rinkes, {Inne H. M. Borel} and Jeroen Korving and Lentjes, {Eef G. W. M.} and Carmen Lopez-Iglesias and Peters, {Peter J.} and {van Santen}, {Hanneke M.} and Vriens, {Menno R.} and Hans Clevers",

note = "Funding Information: ACKNOWLEDGMENTS. We thank Utrecht Portal for Organoid Technology – in particular Anneta Brousali, Jorieke Salij, Kelsey Oosting and Renate Bezemer – for their essential role in securing thyroid tissue from UMCU patients. We thank Stefan van der Elst for flow cytometry assistance; Anko de Graaff and the Hubrecht Imaging Centre for microscopy assistance; Single Cell Discoveries for the provided single-cell sequencing service and support; Utrecht Sequencing for bulk RNA-sequencing services, and Gijs van Son for help with bulk and single-cell RNA-sequencing data mapping. This work was supported by the gravitation program CancerGenomiCs.nl from the Netherlands Organisation for Scientific Research. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",

year = "2021",

month = dec,

day = "21",

doi = "10.1073/pnas.2117017118",

language = "English",

volume = "118",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

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van der Vaart, J, Bosmans, L, Sijbesma, SF, Knoops, K, van de Wetering, WJ, Otten, HG, Begthel, H, Rinkes, IHMB, Korving, J, Lentjes, EGWM, Lopez-Iglesias, C , Peters, PJ, van Santen, HM, Vriens, MR & Clevers, H 2021, 'Adult mouse and human organoids derived from thyroid follicular cells and modeling of Graves' hyperthyroidism', Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 51, 2117017118. https://doi.org/10.1073/pnas.2117017118

Adult mouse and human organoids derived from thyroid follicular cells and modeling of Graves' hyperthyroidism. / van der Vaart, Jelte; Bosmans, Lynn; Sijbesma, Stijn F. et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 118, No. 51, 2117017118, 21.12.2021.

Research output: Contribution to journal › Article › Academic › peer-review

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T1 - Adult mouse and human organoids derived from thyroid follicular cells and modeling of Graves' hyperthyroidism

AU - van der Vaart, Jelte

AU - Bosmans, Lynn

AU - Sijbesma, Stijn F.

AU - Knoops, Kevin

AU - van de Wetering, Willine J.

AU - Otten, Henny G.

AU - Begthel, Harry

AU - Rinkes, Inne H. M. Borel

AU - Korving, Jeroen

AU - Lentjes, Eef G. W. M.

AU - Lopez-Iglesias, Carmen

AU - Peters, Peter J.

AU - van Santen, Hanneke M.

AU - Vriens, Menno R.

AU - Clevers, Hans

N1 - Funding Information: ACKNOWLEDGMENTS. We thank Utrecht Portal for Organoid Technology – in particular Anneta Brousali, Jorieke Salij, Kelsey Oosting and Renate Bezemer – for their essential role in securing thyroid tissue from UMCU patients. We thank Stefan van der Elst for flow cytometry assistance; Anko de Graaff and the Hubrecht Imaging Centre for microscopy assistance; Single Cell Discoveries for the provided single-cell sequencing service and support; Utrecht Sequencing for bulk RNA-sequencing services, and Gijs van Son for help with bulk and single-cell RNA-sequencing data mapping. This work was supported by the gravitation program CancerGenomiCs.nl from the Netherlands Organisation for Scientific Research. Publisher Copyright: © 2021 National Academy of Sciences. All rights reserved.

PY - 2021/12/21

Y1 - 2021/12/21

N2 - 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.

AB - 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.

KW - thyroid

KW - organoids

KW - Graves' disease

KW - STEM-CELLS

KW - IN-VITRO

KW - TSH

KW - GENERATION

KW - DIFFERENTIATION

KW - PROLIFERATION

KW - REGENERATION

KW - POPULATION

KW - FOLLICLES

KW - CULTURES

U2 - 10.1073/pnas.2117017118

DO - 10.1073/pnas.2117017118

M3 - Article

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SN - 0027-8424

VL - 118

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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M1 - 2117017118

ER -