CoChat
Sign Up
Cited by 64Pluripotent Stem Cells ResearchThyroid Disorders and TreatmentsDevelopmental Biology and Gene Regulation

The DOI matches its Crossref record; the references it cites are not checked yet.

Transplantable human thyroid organoids generated from embryonic stem cells to rescue hypothyroidism

Open access
Romitti, Mírian, Tourneur, Adrien, de Faria da Fonseca, Barbara, Doumont, Gilles, Gillotay, Pierre, Liao, Xiao-Hui, Eski, Sema Elif, Van Simaeys, Gaetan, Chomette, Laura, Lasolle, Helene, Monestier, Olivier, Kasprzyk, Dominika Figini, Detours, Vincent, Singh, Sumeet Pal, Goldman, Serge, Refetoff, Samuel, Costagliola, Sabine·2022·Nature Communications
DOI 10.1038/s41467-022-34776-7PMC PMC9672394

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

The thyroid gland captures iodide in order to synthesize hormones that act on almost all tissues and are essential for normal growth and metabolism. Low plasma levels of thyroid hormones lead to hypothyroidism, which is one of the most common disorder in humans and is not always satisfactorily treated by lifelong hormone replacement. Therefore, in addition to the lack of in vitro tractable models to study human thyroid development, differentiation and maturation, functional human thyroid organoids could pave the way to explore new therapeutic approaches. Here we report the generation of transplantable thyroid organoids derived from human embryonic stem cells capable of restoring plasma thyroid hormone in athyreotic mice as a proof of concept for future therapeutic development.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-022-34776-7

Cites

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Thyroid organoids have a strong regenerative capacity in vivo and provide proof of concept for future therapeutic development.

    “These studies suggest that thyroid organoids have a strong regenerative capacity in vivo and provided the proof of concept for future therapeutic development (69).”

    From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [69]

    The Results (Assessment of in vivo functionality) show that transplanted human thyroid organoids increased thyroid hormone levels in mice with ablated thyroid glands, and the Discussion calls this a proof of concept for future therapeutic development. But T4 remained below control levels and systemic recovery was partial, so describing the organoids as having a broadly 'strong regenerative capacity in vivo' overstates the demonstrated result. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Transplantable thyroid organoids derived from human ESCs restored plasma thyroid hormone levels in athyreotic mice.

    “More recently, transplantable thyroid organoids derived from human ESCs restored plasma TH levels in athyreotic mice (69).”

    From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [69]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

The citation lists haven’t been fetched yet

References 90 · Cited by 64

Research works printed but not linked: 76

  1. Vanderpump, M. P. J. The epidemiology of thyroid disease. Br. Med. Bull. 99, 39–51 (2011). · DOI · Paper page
  2. Garmendia Madariaga, A., Santos Palacios, S., Guillén-Grima, F. & Galofré, J. C. The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. J. Clin. Endocrinol. Metab. 99, 923–931 (2014). · DOI · Paper page
  3. Dew, R. et al. Clinical, behavioural and pharmacogenomic factors influencing the response to levothyroxine therapy in patients with primary hypothyroidism-protocol for a systematic review. Syst. Rev. 6, 60 (2017). · DOI
  4. Kraut, E. & Farahani, P. A systematic review of clinical practice guidelines’ recommendations on levothyroxine therapy alone versus combination therapy (LT4 plus LT3) for hypothyroidism. Clin. Investigative Med. 38, E305-E313 (2015). · DOI
  5. Biondi, B. & Wartofsky, L. Treatment with thyroid hormone. Endocr. Rev. 35, 433–512 (2014). · DOI · Paper page
  6. Taylor, P. N. et al. Combination thyroid hormone replacement; knowns and unknowns. Front. Endocrinol. 10, 706 (2019). · DOI
  7. Bauer, A. J. & Wassner, A. J. Thyroid hormone therapy in congenital hypothyroidism and pediatric hypothyroidism. Endocrine 66, 51–62 (2019). · DOI
  8. Longmire, T. A. et al. Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells. Cell Stem Cell 10, 398–411 (2012). · DOI · Paper page
  9. Ma, R., Latif, R. & Davies, T. F. Thyroid follicle formation and thyroglobulin expression in multipotent endodermal stem cells. Thyroid 23, 385–391 (2013). · DOI
  10. Dame, K. et al. Thyroid progenitors are robustly derived from embryonic stem cells through transient, developmental stage-specific overexpression of Nkx2-1. Stem Cell Rep. 8, 216–225 (2017). · DOI
  11. Kurmann, A. A. et al. Regeneration of thyroid function by transplantation of differentiated pluripotent stem cells. Cell Stem Cell 17, 527–542 (2015). · DOI · Paper page
  12. Ma, R., Latif, R. & Davies, T. F. Human embryonic stem cells form functional thyroid follicles. Thyroid 25, 455–461 (2015). · DOI
  13. Ma, R., Morshed, S. A., Latif, R. & Davies, T. F. TAZ induction directs differentiation of thyroid follicular cells from human embryonic stem cells. Thyroid 27, 292–299 (2017). · DOI
  14. Serra, M. et al. Pluripotent stem cell differentiation reveals distinct developmental pathways regulating Lung-Versus Thyroid-Lineage specification. Development 144, 3879–3893 (2017).
  15. Ma, R., Shi, R., Morshed, S. A., Latif, R. & Davies, T. F. Derivation and 97% purification of human thyroid cells from dermal fibroblasts. Front. Endocrinol. (Lausanne) 11, 446 (2020). · DOI
  16. Arauchi, A., Matsuura, K., Shimizu, T. & Okano, T. Functional thyroid follicular cells differentiation from human-induced pluripotent stem cells in suspension culture. Front. Endocrinol. 8, 103 (2017). · DOI
  17. Ogundipe, V. M. L. et al. Generation and differentiation of adult tissue-derived human thyroid organoids. Stem Cell Rep. 16, 913–925 (2021). · DOI
  18. Liang, J. et al. Modeling human thyroid development by fetal tissue-derived organoid culture. Adv. Sci. 9, 2105568 (2022). · DOI
  19. van der Vaart, J. et al. Adult mouse and human organoids derived from thyroid follicular cells and modeling of Graves’ hyperthyroidism. Proc. Natl Acad. Sci. 118, e2117017118 (2021). · DOI
  20. Bondue, A. et al. Mesp1 acts as a master regulator of multipotent cardiovascular progenitor specification. Cell Stem Cell 3, 69–84 (2008). · DOI
  21. Mazzoni, E. O. et al. Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity. Nat. Neurosci. 16, 1219–1227 (2013). · DOI
  22. Moreau, T. et al. Large-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming. Nat. Commun. 7, 11208 (2016). · DOI
  23. Pawlowski, M. et al. Inducible and deterministic forward programming of human pluripotent stem cells into neurons, skeletal myocytes, and oligodendrocytes. Stem Cell Rep. 8, 803–812 (2017). · DOI
  24. de Felice, M. & di Lauro, R. Thyroid development and its disorders: genetics and molecular mechanisms. Endocr. Rev. 25, 722–746 (2004). · DOI
  25. Goulburn, A. L. et al. A targeted NKX2.1 human embryonic stem cell reporter line enables identification of human basal forebrain derivatives. Stem Cells 29, 462–473 (2011). · DOI
  26. Vassart, G. & Dumont, J. E. The thyrotropin receptor and the regulation of thyrocyte function and growth. 13, 596–611 (1992). · DOI
  27. Mori, K., Mori, M., Stone, S., Braverman, L. & DeVito, W. Increased expression of tumor necrosis factor-alpha and decreased expression of thyroglobulin and thyroid peroxidase mRNA levels in the thyroids of iodide-treated BB/Wor rats. Eur. J. Endocrinol. 139, 539-545 (1998). · DOI
  28. Dohán, O. et al. The sodium/iodide symporter (NIS): Characterization, regulation, and medical significance. Endocr. Rev. 24, 48–77 (2003). · DOI
  29. Mincione, G. et al. EGF and TGF-β1 effects on thyroid function. J. Thyroid Res. 2011, 431718 https://doi.org/10.4061/2011/431718 (2011). · DOI
  30. Faria, M. et al. TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells. PLoS ONE 15, e0228794–e0228794 (2020). · DOI
  31. Romitti, M. et al. Single-cell trajectory inference guided enhancement of thyroid maturation in vitro using TGF-beta inhibition. Front. Endocrinol. 12, (2021). · DOI
  32. Dom, G. et al. Transcriptomic signature of human embryonic thyroid reveals transition from differentiation to functional maturation. Front. Cell Dev. Biol. 9, 669354 (2021). · DOI
  33. Haerlingen, B. et al. Small-molecule screening in zebrafish embryos identifies signaling pathways regulating early thyroid development. Thyroid 29, 1683–1703 (2019). · DOI
  34. Vandernoot, I. et al. Enhanced canonical wnt signaling during early zebrafish development perturbs the interaction of cardiac mesoderm and pharyngeal endoderm and causes thyroid specification defects. Thyroid 31, 420-438 (2021). · DOI
  35. Smith, T. J. Insulin-like growth factor pathway and the thyroid. Front. Endocrinol. 12, 653627 (2021). · DOI
  36. Biernacka, A., Dobaczewski, M. & Frangogiannis, N. G. TGF-β signaling in fibrosis. Growth Factors 29, 196–202 (2011). · DOI
  37. Frangogiannis, N. G. Transforming growth factor–β in tissue fibrosis. J. Exp. Med. 217, e20190103 (2020). · DOI
  38. Szinnai, G. et al. Sodium/iodide symporter (NIS) gene expression is the limiting step for the onset of thyroid function in the human fetus. J. Clin. Endocrinol. Metab. 92, 70–76 (2007). · DOI
  39. Brandt, M. P. et al. Micro-single-photon emission computed tomography image acquisition and quantification of sodium-iodide symporter-mediated radionuclide accumulation in mouse thyroid and salivary glands. Thyroid 22, 617–624 (2012). · DOI
  40. Berry, M. J., Kates, A.-L. & Larsen, P. R. Thyroid hormone regulates type I deiodinase messenger RNA in rat liver. Mol. Endocrinol. 4, 743–748 (1990). · DOI
  41. Maia, A. L., Kieffer, J. D., Harney, J. W. & Larsen, P. R. Effect of 3,5,3’-Triiodothyronine (T3) administration on dio1 gene expression and T3 metabolism in normal and type 1 deiodinase-deficient mice. Endocrinology 136, 4842–4849 (1995). · DOI
  42. Brons, I. G. M. et al. Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448, 191–195 (2007). · DOI
  43. Buecker, C. & Geijsen, N. Different flavors of pluripotency, molecular mechanisms, and practical implications. Cell Stem Cell 7, 559–564 (2010). · DOI
  44. Hanna, J. et al. Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proc. Natl Acad. Sci. 107, 9222–9227 (2010). · DOI
  45. Tesar, P. J. et al. New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448, 196–199 (2007). · DOI
  46. Rossant, J. Stem cells and early lineage development. Cell 132, 527–531 (2008). · DOI
  47. Bao, S. et al. Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells. Nature 461, 1292–1295 (2009). · DOI
  48. Guo, G. et al. Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development 136, 1063–1069 (2009). · DOI
  49. Hayashi, K. & Surani, M. A. Self-renewing epiblast stem cells exhibit continual delineation of germ cells with epigenetic reprogramming in vitro. Development 136, 3549–3556 (2009). · DOI
  50. Nichols, J. & Smith, A. Naive and primed pluripotent states. Cell Stem Cell 4, 487–492 (2009). · DOI
  51. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998). · DOI
  52. Gabdoulline, R. et al. Differences in the early development of human and mouse embryonic stem cells. PLoS ONE 10, e0140803 (2015). · DOI
  53. Sun, L., Fu, X., Ma, G. & Hutchins, A. P. Chromatin and epigenetic rearrangements in embryonic stem cell fate transitions. Front. Cell Dev. Biol. 9, 637309 (2021). · DOI
  54. Silva, J. et al. Nanog is the gateway to the pluripotent ground state. Cell 138, 722–737 (2009). · DOI · Paper page
  55. Chen, G. et al. Chemically defined conditions for human iPSC derivation and culture. Nat. Methods 8, 424–429 (2011). · DOI · Paper page
  56. Kinoshita, M. et al. Capture of mouse and human stem cells with features of formative pluripotency. Cell Stem Cell 28, 453–471.e8 (2021). · DOI
  57. Saito, Y. et al. Development of a functional thyroid model based on an organoid culture system. Biochem. Biophys. Res. Commun. 497, 783–789 (2018). · DOI
  58. Khoruzhenko, A. et al. Functional model of rat thyroid follicles cultured in Matrigel. Endocr. Connect. 10, 550–578 (2021). · DOI
  59. Coclet, J., Foureau, F., Ketelbant, P., Galand, P. & Dumont, J. E. Cell population kinetics in dog and human adult thyroid. Clin. Endocrinol. 31, 655–665 (1989). · DOI
  60. Opitz, R. et al. Transgenic zebrafish illuminate the dynamics of thyroid morphogenesis and its relationship to cardiovascular development. Dev. Biol. 372, 203–216 (2012). · DOI
  61. Eggo, M. C., Bachrach, L. K. & Burrow, G. N. Interaction of TSH, insulin and insulin-like growth factors in regulating thyroid growth and function. Growth Factors 2, 99–109 (1990). · DOI
  62. Ock, S. et al. Thyrocyte-specific deletion of insulin and IGF-1 receptors induces papillary thyroid carcinoma-like lesions through EGFR pathway activation. Int. J. Cancer 143, 2458–2469 (2018). · DOI
  63. Berthod, F., Germain, L., Tremblay, N. & Auger, F. A. Extracellular matrix deposition by fibroblasts is necessary to promote capillary-like tube formation in vitro. J. Cell. Physiol. 207, 491–498 (2006). · DOI
  64. Costa-Almeida, R., Granja, P., Soares, R. & Guerreiro, S. Cellular strategies to promote vascularisation in tissue engineering applications. Eur. Cells Mater. 28, 51–66 (2014). · DOI
  65. Njauw, C.-N., Yuan, H., Zheng, L., Yao, M. & Martins-Green, M. Origin of periendothelial cells in microvessels derived from human microvascular endothelial cells. Int. J. Biochem. Cell Biol. 40, 710–720 (2008). · DOI
  66. Hurley, J. R., Balaji, S. & Narmoneva, D. A. Complex temporal regulation of capillary morphogenesis by fibroblasts. Am. J. of Physiol. Cell Physiol. 299, C444–C453 (2010). · DOI
  67. Moroni, L. et al. SCREENED: a multistage model of thyroid gland function for screening endocrine-disrupting chemicals in a biologically sex-specific manner. Int. J. Mol. Sci. 21, 3648 (2020). · DOI
  68. Campos, P. B., Sartore, R. C., Abdalla, S. N. & Rehen, S. K. Chromosomal spread preparation of human embryonic stem cells for karyotyping. J. Vis. Exp. 31,1512 (2009). · DOI
  69. Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120 (2014). · DOI · Paper page
  70. Kim, D., Langmead, B. & Salzberg, S. L. HISAT: a fast spliced aligner with low memory requirements. Nat. Methods 12, 357–360 (2015). · DOI · Paper page
  71. Anders, S., Pyl, P. T. & Huber, W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015). · DOI · Paper page
  72. Ge, S. X., Son, E. W. & Yao, R. iDEP: an integrated web application for differential expression and pathway analysis of RNA-Seq data. BMC Bioinformatics 19, 534 (2018). · DOI
  73. Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587.e29 (2021). · DOI · Paper page
  74. Efremova, M., Vento-Tormo, M., Teichmann, S. A. & Vento-Tormo, R. CellPhoneDB: inferring cell–cell communication from combined expression of multi-subunit ligand–receptor complexes. Nat. Protocols 15, 1484–1506 (2020). · DOI · Paper page
  75. Ferrara, A. M. et al. Changes in thyroid status during perinatal development of MCT8-deficient male mice. Endocrinology 154, 2533–2541 (2013). · DOI
  76. Pohlenz, J. et al. Improved radioimmunoassay for measurement of mouse thyrotropin in serum: strain differences in thyrotropin concentration and thyrotroph sensitivity to thyroid hormone. Thyroid 9, 1265–1271 (1999). · DOI

Metadata

Authors
Romitti, M., Tourneur, A., de Faria da Fonseca, B., Doumont, G., Gillotay, P., Liao, X.-H., Eski, S. E., Van Simaeys, G., Chomette, L., Lasolle, H., Monestier, O., Kasprzyk, D. F., Detours, V., Singh, S. P., Goldman, S., Refetoff, S., & Costagliola, S.
Affiliations
  • Université Libre de Bruxelles (BE)
  • University of Chicago (US)
Corresponding author
Costagliola, Sabine
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-11-17
Volume
13
Issue
1
Pages
7057-7057
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-34776-7
PMC
PMC9672394
OpenAlex
W4309236286
Cited by
64
References
90
Citations by year
2026: 14 · 2025: 15 · 2024: 17 · 2023: 15 · 2022: 3
FWCI
4.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Fonds Erasme
  • Waalse Gewest
  • European Commission (HORIZON2020, 825745)
  • Fonds De La Recherche Scientifique - FNRS (34772792)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • National Institutes of Health (DK 15070)
  • European Regional Development Fund
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK015070)
  • Division of Civil, Mechanical and Manufacturing Innovation
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
human embryonic stem cells, hypothyroidism, thyroid transplantation, athyroidism, thyroid hormones, thyroid development, organoid transplantation, mouse model
MeSH terms
Animals, Humans, Hypothyroidism, Organoids, Thyroid Hormones, Mice, Embryonic Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review