Generation of functional thyroid from embryonic stem cells
Open accessAbstract
The primary function of the thyroid gland is to metabolize iodide by synthesizing thyroid hormones, which are critical regulators of growth, development and metabolism in almost all tissues. So far, research on thyroid morphogenesis has been missing an efficient stem-cell model system that allows for the in vitro recapitulation of the molecular and morphogenic events regulating thyroid follicular-cell differentiation and subsequent assembly into functional thyroid follicles. Here we report that a transient overexpression of the transcription factors NKX2-1 and PAX8 is sufficient to direct mouse embryonic stem-cell differentiation into thyroid follicular cells that organize into three-dimensional follicular structures when treated with thyrotropin. These in vitro-derived follicles showed appreciable iodide organification activity. Importantly, when grafted in vivo into athyroid mice, these follicles rescued thyroid hormone plasma levels and promoted subsequent symptomatic recovery. Thus, mouse embryonic stem cells can be induced to differentiate into thyroid follicular cells in vitro and generate functional thyroid tissue.
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Overexpression of transcription factors NKX2.1 and PAX8 in these progenitors led to fully differentiated follicular cells expressing thyroid-specific genes such as TSH receptor, sodium/iodide symporter, and thyroglobulin.
“The subsequent overexpression of the transcription factors NKX2.1 and PAX8 (67) led to fully differentiated follicular cells that express thyroid-specific genes such as TSH receptor, sodium/iodide symporter, and thyroglobulin.”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [67]
In “In vitro thyroid cells differentiation,” the paper reports that NKX2.1 and PAX8 co-overexpression up-regulated Tshr, Slc5a5 (NIS), and Tg and drove cells toward a thyroid follicular-cell lineage. But the same section and “In vitro formation of functional follicles” say subsequent TSH treatment was vital to complete follicular maturation; overexpression alone did not produce the fully developed follicular structures implied by the claim. (LLM, conf=0.87)
Experimental — accuracy not yet measuredExposure to human TSH causes these cells to organize in a 3D follicular architecture.
“Exposure to human TSH causes these cells to organize in a 3D follicular architecture that was grafted under the kidney capsules of hypothyroid mice.”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [67]
In hypothyroid mice grafted with these cells, four weeks later T4 levels became detectable and serum TSH levels were reduced compared to before grafting.
“Four weeks later, T4 levels became detectable and serum TSH levels were reduced when compared to levels before grafting (67).”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [67]
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- Authors
- Antonica, F., Kasprzyk, D. F., Opitz, R., Iacovino, M., Liao, X.-H., Dumitrescu, A. M., Refetoff, S., Peremans, K., Manto, M., Kyba, M., & Costagliola, S.
- Affiliations
- Université Libre de Bruxelles (BE)
- University of Minnesota (US)
- University of Chicago (US)
- Ghent University (BE)
- Corresponding author
- Costagliola, Sabine
- ORCID
- Venue
- Nature
- Published
- 2012-10-10
- Volume
- 491
- Issue
- 7422
- Pages
- 66-71
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3687105
- OpenAlex
- W2155574792
- Cited by
- 359
- References
- 78
- Citations by year
- 2026: 18 · 2025: 20 · 2024: 23 · 2023: 26 · 2022: 33 · 2021: 28 · 2020: 33 · 2019: 24 · 2018: 19 · 2017: 18 · 2016: 26 · 2015: 35 · 2014: 27 · 2013: 25 · 2012: 3
- FWCI
- 11.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Iris (University of Trento) (submittedVersion)
- Funders
- Fonds De La Recherche Scientifique - FNRS
- National Institutes of Health (DK 15070)
- Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 15070, R37DK015070, F32DK091016, DK91016, R01DK015070)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- embryonic stem cells, thyroid follicular cells, TTF-1, PAX8, transcription factors, thyroid-stimulating hormone, iodide organification, thyroid hormone synthesis, thyroid development, congenital hypothyroidism, regenerative medicine, stem cell differentiation
- MeSH terms
- PAX8 Transcription Factor, Thyroid Nuclear Factor 1, Animals, Cell Differentiation, Disease Models, Animal, Female, Humans, Hypothyroidism, Nuclear Proteins, Thyroid Gland, Thyrotropin, Thyroxine, Transcription Factors, Mice, Paired Box Transcription Factors, Embryonic Stem Cells
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