Organoids are complex multicellular structures that stem cells self-organize in three-dimensional (3D) cultures into anatomical structures and functional units similar to those seen in the organs from which they originate. This review describes the construction of thyroid organoids and the research progress that has occurred in models of thyroid-related disease. As a novel tool for modeling in a 3D multicellular environment, organoids help provide some useful references for the study of the pathogenesis of thyroid disease.

Department of Endocrinology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

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Kurmann AA, Serra M, Hawkins F, Rankin SA, Mori M, Astapova I, Ullas S, et al. Regeneration of thyroid function by transplantation of differentiated pluripotent stem cells. Cell Stem Cell. 2015;17:527–542. doi: 10.1016/j.stem.2015.09.004. PubMed DOI PMC

Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459:262–265. doi: 10.1038/nature07935. PubMed DOI

Li M, Izpisua Belmonte JC. Organoids - preclinical models of human disease. N Engl J Med. 2019;380:569–579. doi: 10.1056/NEJMra1806175. PubMed DOI

Taylor PN, Albrecht D, Scholz A, Gutierrez-Buey G, Lazarus JH, Dayan CM, Okosieme OE. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol. 2018;14:301–316. doi: 10.1038/nrendo.2018.18. PubMed DOI

Duval K, Grover H, Han LH, Mou Y, Pegoraro AF, Fredberg J, Chen Z. Modeling physiological events in 2D vs. 3D cell culture. Physiology (Bethesda) 2017;32:266–277. doi: 10.1152/physiol.00036.2016. PubMed DOI PMC

Antonica F, Kasprzyk DF, Opitz R, Iacovino M, Liao XH, Dumitrescu AM, Refetoff S, et al. Generation of functional thyroid from embryonic stem cells. Nature. 2012;491:66–71. doi: 10.1038/nature11525. PubMed DOI PMC

Samimi H, Atlasi R, Parichehreh-Dizaji S, Khazaei S, Akhavan Rahnama M, Seifirad S, Haghpanah V. A systematic review on thyroid organoid models: time-trend and its achievements. Am J Physiol Endocrinol Metab. 2021;320:E581–E590. doi: 10.1152/ajpendo.00479.2020. PubMed DOI

Dame K, Cincotta S, Lang AH, Sanghrajka RM, Zhang L, Choi J, Kwok L, et al. Thyroid progenitors are robustly derived from embryonic stem cells through transient, developmental stage-specific overexpression of Nkx2-1. Stem Cell Reports. 2017;8:216–225. doi: 10.1016/j.stemcr.2016.12.024. PubMed DOI PMC

Ma R, Morshed SA, Latif R, Davies TF. Thyroid cell differentiation from murine induced pluripotent stem cells. Front Endocrinol (Lausanne) 2015;6:56. doi: 10.3389/fendo.2015.00056. PubMed DOI PMC

Ma R, Latif R, Davies TF. Human embryonic stem cells form functional thyroid follicles. Thyroid. 2015;25:455–461. doi: 10.1089/thy.2014.0537. PubMed DOI PMC

Ogundipe VML, Groen AH, Hosper N, Nagle PWK, Hess J, Faber H, Jellema AL, et al. Generation and differentiation of adult tissue-derived human thyroid organoids. Stem Cell Reports. 2021;16:913–925. doi: 10.1016/j.stemcr.2021.02.011. PubMed DOI PMC

Liang J, Qian J, Yang L, Chen X, Wang X, Lin X, Wang X, Zhao B. Modeling Human Thyroid Development by Fetal Tissue-Derived Organoid Culture. Adv Sci (Weinh) 2022;9:e2105568. doi: 10.1002/advs.202105568. PubMed DOI PMC

Longmire TA, Ikonomou L, Hawkins F, Christodoulou C, Cao Y, Jean JC, Kwok LW, et al. Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells. Cell Stem Cell. 2012;10:398–411. doi: 10.1016/j.stem.2012.01.019. PubMed DOI PMC

Dom G, Dmitriev P, Lambot MA, Van Vliet G, Glinoer D, Libert F, Lefort A, Dumont JE, Maenhaut C. Transcriptomic signature of human embryonic thyroid reveals transition from differentiation to functional maturation. Front Cell Dev Biol. 2021;9:669354. doi: 10.3389/fcell.2021.669354. PubMed DOI PMC

Sjölin G, Holmberg M, Törring O, Byström K, Khamisi S, de Laval D, Abraham-Nordling M, et al. The long-term outcome of treatment for Graves’ hyperthyroidism. Thyroid. 2019;29:1545–1557. doi: 10.1089/thy.2019.0085. PubMed DOI

van der Vaart J, Bosmans L, Sijbesma SF, Knoops K, van de Wetering WJ, Otten HG, Begthel H, et al. Adult mouse and human organoids derived from thyroid follicular cells and modeling of Graves’ hyperthyroidism. Proc Natl Acad Sci U S A. 2021;118:e2117017118. doi: 10.1073/pnas.2117017118. PubMed DOI PMC

Ichioka H, Ida Y, Watanabe M, Ohguro H, Hikage F. Prostaglandin F2α and EP2 agonists, and a ROCK inhibitor modulate the formation of 3D organoids of Grave’s orbitopathy related human orbital fibroblasts. Exp Eye Res. 2021;205:108489. doi: 10.1016/j.exer.2021.108489. PubMed DOI

Dew R, Okosieme O, Dayan C, Eligar V, Khan I, Razvi S, Pearce S, Wilkes S. Clinical, behavioural and pharmacogenomic factors influencing the response to levothyroxine therapy in patients with primary hypothyroidism-protocol for a systematic review. Syst Rev. 2017;6:60. doi: 10.1186/s13643-017-0457-z. PubMed DOI PMC

Watt T, Cramon P, Hegedüs L, Bjorner JB, Bonnema SJ, Rasmussen Å K, Feldt-Rasmussen U, Groenvold M. The thyroid-related quality of life measure ThyPRO has good responsiveness and ability to detect relevant treatment effects. J Clin Endocrinol Metab. 2014;99:3708–3717. doi: 10.1210/jc.2014-1322. PubMed DOI

Romitti M, Tourneur A, de Faria da Fonseca B, Doumont G, Gillotay P, Liao XH, Eski SE, et al. Transplantable human thyroid organoids generated from embryonic stem cells to rescue hypothyroidism. Nat Commun. 2022;13:7057. doi: 10.1038/s41467-022-34776-7. PubMed DOI PMC

Kim S, Park YW, Schiff BA, Doan DD, Yazici Y, Jasser SA, Younes M, et al. An orthotopic model of anaplastic thyroid carcinoma in athymic nude mice. Clin Cancer Res. 2005;11:1713–1721. doi: 10.1158/1078-0432.CCR-04-1908. PubMed DOI

Jian M, Ren L, He G, Lin Q, Tang W, Chen Y, Chen J, et al. A novel patient-derived organoids-based xenografts model for preclinical drug response testing in patients with colorectal liver metastases. J Transl Med. 2020;18:234. doi: 10.1186/s12967-020-02407-8. PubMed DOI PMC

Jankovic J, Dettwiler M, Fernández MG, Tièche E, Hahn K, April-Monn S, Dettmer MS, et al. Validation of immunohistochemistry for canine proteins involved in thyroid iodine uptake and their expression in canine Follicular Cell Thyroid Carcinomas (FTCs) and FTC-derived organoids. Vet Pathol. 2021;58:1172–1180. doi: 10.1177/03009858211018813. PubMed DOI

Chen D, Tan Y, Li Z, Li W, Yu L, Chen W, Liu Y, et al. Organoid cultures derived from patients with papillary thyroid cancer. J Clin Endocrinol Metab. 2021;106:1410–1426. doi: 10.1210/clinem/dgab020. PubMed DOI

Chen D, Su X, Zhu L, Jia H, Han B, Chen H, Liang Q, et al. Papillary thyroid cancer organoids harboring BRAF(V600E) mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapies. J Transl Med. 2023;21:9. doi: 10.1186/s12967-022-03848-z. PubMed DOI PMC

Pecce V, Sponziello M, Bini S, Grani G, Durante C, Verrienti A. Establishment and maintenance of thyroid organoids from human cancer cells. STAR Protoc. 2022;3:101393. doi: 10.1016/j.xpro.2022.101393. PubMed DOI PMC

Lai X, Xia Y, Zhang B, Li J, Jiang Y. A meta-analysis of Hashimoto’s thyroiditis and papillary thyroid carcinoma risk. Oncotarget. 2017;8:62414–62424. doi: 10.18632/oncotarget.18620. PubMed DOI PMC

He X, Xiong C, Liu A, Zhao W, Xia X, Peng S, Li C, et al. Phagocytosis deficiency of macrophages in NOD.H-2(h4) mice accelerates the severity of iodine-induced autoimmune thyroiditis. Biol Trace Elem Res. 2018;184:196–205. doi: 10.1007/s12011-017-1183-z. PubMed DOI

Wang X, Liu H, Zhang Y, Li J, Teng X, Liu A, Yu X, Shan Z, Teng W. Effects of isolated positive maternal thyroglobulin antibodies on brain development of offspring in an experimental autoimmune thyroiditis model. Thyroid. 2015;25:551–558. doi: 10.1089/thy.2014.0310. PubMed DOI

Vilgelm AE, Bergdorf K, Wolf M, Bharti V, Shattuck-Brandt R, Blevins A, Jones C, et al. Fine-needle aspiration-based patient-derived cancer organoids. iScience. 2020;23:101408. doi: 10.1016/j.isci.2020.101408. PubMed DOI PMC

Xiao H, Liang J, Liu S, Zhang Q, Xie F, Kong X, Guo S, et al. Proteomics and organoid culture reveal the underlying pathogenesis of hashimoto’s thyroiditis. Front Immunol. 2021;12:784975. doi: 10.3389/fimmu.2021.784975. PubMed DOI PMC

Shin W, Wu A, Min S, Shin YC, Fleming RYD, Eckhardt SG, Kim HJ. Spatiotemporal gradient and instability of Wnt induce heterogeneous growth and differentiation of human intestinal organoids. iScience. 2020;23:101372. doi: 10.1016/j.isci.2020.101372. PubMed DOI PMC

Serex L, Sharma K, Rizov V, Bertsch A, McKinney JD, Renaud P. Microfluidic-assisted bioprinting of tissues and organoids at high cell concentrations. Biofabrication. 2021:13. doi: 10.1088/1758-5090/abca80. PubMed DOI

Riley A, Green V, Cheah R, McKenzie G, Karsai L, England J, Greenman J. A novel microfluidic device capable of maintaining functional thyroid carcinoma specimens ex vivo provides a new drug screening platform. BMC Cancer. 2019;19:259. doi: 10.1186/s12885-019-5465-z. PubMed DOI PMC

He A, Powell S, Kyle M, Rose M, Masmila E, Estrada V, Sicklick JK, Molinolo A, Kaushal S. Cryopreservation of viable human tissues: Renewable resource for viable tissue, cell lines, and organoid development. Biopreserv Biobank. 2020;18:222–227. doi: 10.1089/bio.2019.0062. PubMed DOI PMC

Kühnlenz J, Karwelat D, Steger-Hartmann T, Raschke M, Bauer S, Vural Ö, Marx U, Tinwell H, Bars R. A microfluidic thyroid-liver platform to assess chemical safety in humans. Altex. 2023;40:61–82. doi: 10.14573/altex.2108261. PubMed DOI

Spaletta G, Sofroniou M, Barbaro F, Di Conza G, Mosca S, Toni R. A computational template for 3D modelling of the vascular scaffold of the human thyroid gland. Tissue Eng Part A. 2023;29:47–57. doi: 10.1089/ten.TEA.2022.0148. PubMed DOI

Riley A, Jones H, England J, Kuvshinov D, Green V, Greenman J. Identification of soluble tissue-derived biomarkers from human thyroid tissue explants maintained on a microfluidic device. Oncol Lett. 2021;22:780. doi: 10.3892/ol.2021.13041. PubMed DOI PMC