Regeneration of Thyroid Function by Transplantation of Differentiated Pluripotent Stem Cells
Open accessAbstract
Differentiation of functional thyroid epithelia from pluripotent stem cells (PSCs) holds the potential for application in regenerative medicine. However, progress toward this goal is hampered by incomplete understanding of the signaling pathways needed for directed differentiation without forced overexpression of exogenous transgenes. Here we use mouse PSCs to identify key conserved roles for BMP and FGF signaling in regulating thyroid lineage specification from foregut endoderm in mouse and Xenopus. Thyroid progenitors derived from mouse PSCs can be matured into thyroid follicular organoids that provide functional secretion of thyroid hormones in vivo and rescue hypothyroid mice after transplantation. Moreover, by stimulating the same pathways, we were also able to derive human thyroid progenitors from normal and disease-specific iPSCs generated from patients with hypothyroidism resulting from NKX2-1 haploinsufficiency. Our studies have therefore uncovered the regulatory mechanisms that underlie early thyroid organogenesis and provide a significant step toward cell-based regenerative therapy for hypothyroidism.
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.
Integrity signals
Registry
Cites
Statistics
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.
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?
Mouse ESC-derived thyroid progenitors matured into thyroid follicular organoids that provided functional secretion of thyroid hormone in vivo and rescued hypothyroid mice after transplantation.
“In subsequent studies (68), thyroid progenitors derived from mouse ESCs were matured into thyroid follicular organoids that provided functional secretion of TH in vivo and rescued hypothyroid mice after transplantation.”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [68]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 41 · Cited by 204
Research works printed but not linked: 35
- Arufe MC Lu M Kubo A Keller G Davies TF Lin RY Directed differentiation of mouse embryonic stem cells into thyroid follicular cells Endocrinology 2006 147 3007 3015 16497809 PMC1592134
- Arufe MC Lu M Lin RY Differentiation of murine embryonic stem cells to thyrocytes requires insulin and insulin-like growth factor-1 Biochem Biophys Res Commun 2009 381 264 270 19232325 PMC2661622
- Bachiller D Klingensmith J Shneyder N Tran U Anderson R Rossant J De Robertis EM The role of chordin/Bmp signals in mammalian pharyngeal development and DiGeorge syndrome Development 2003 130 3567 3578 12810603
- Bilodeau M Shojaie S Ackerley C Post M Rossant J Identification of a proximal progenitor population from murine fetal lungs with clonogenic and multilineage differentiation potential Stem cell reports 2014 3 634 649 25358791 PMC4223706
- Bouchard M Souabni A Busslinger M Tissue-specific expression of cre recombinase from the Pax8 locus Genesis 2004 38 105 109 15048807
- Celli G LaRochelle WJ Mackem S Sharp R Merlino G Soluble dominant-negative receptor uncovers essential roles for fibroblast growth factors in multi-organ induction and patterning EMBO J 1998 17 1642 1655 9501086 PMC1170512
- Crane AM Kramer P Bui JH Chung WJ Li XS Gonzalez-Garay ML Hawkins F Liao W Mora D Choi S Targeted Correction and Restored Function of the CFTR Gene in Cystic Fibrosis Induced Pluripotent Stem Cells Stem cell reports 2015 4 569 577 25772471 PMC4400651
- Fagman H Liao J Westerlund J Andersson L Morrow BE Nilsson M The 22q11 deletion syndrome candidate gene Tbx1 determines thyroid size and positioning Hum Mol Genet 2007 16 276 285 17164259
- Fagman H Nilsson M Morphogenesis of the thyroid gland Molecular and cellular endocrinology 2010 323 35 54 20026174
- Goss AM Tian Y Tsukiyama T Cohen ED Zhou D Lu MM Yamaguchi TP Morrisey EE Wnt2/2b and beta-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut Dev Cell 2009 17 290 298 19686689 PMC2763331
- Green MD Chen A Nostro MC d’Souza SL Schaniel C Lemischka IR Gouon-Evans V Keller G Snoeck HW Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells Nat Biotechnol 2011 29 267 272 21358635 PMC4866999
- Hamvas A Deterding RR Wert SE White FV Dishop MK Alfano DN Halbower AC Planer B Stephan MJ Uchida DA Heterogeneous Pulmonary Phenotypes Associated With Mutations in the Thyroid Transcription Factor Gene NKX2-1 Chest 2013 144 794 804 23430038 PMC3760742
- Hilfer SR Iszard LB Hilfer EK Follicle formation in the embryonic chick thyroid. II. Reorganization after dissociation Zeitschrift fur Zellforschung und mikroskopische Anatomie 1968 92 256 269 4907211
- Huang SX Islam MN O’Neill J Hu Z Yang YG Chen YW Mumau M Green MD Vunjak-Novakovic G Bhattacharya J Efficient generation of lung and airway epithelial cells from human pluripotent stem cells Nat Biotechnol 2014 32 84 91 24291815 PMC4101921
- Jiang N Hu Y Liu X Wu Y Zhang H Chen G Liang J Lu X Liu S Differentiation of E14 mouse embryonic stem cells into thyrocytes in vitro Thyroid 2010 20 77 84 19886789
- Kameda Y Ito M Nishimaki T Gotoh N FRS2alpha is required for the separation, migration, and survival of pharyngeal-endoderm derived organs including thyroid, ultimobranchial body, parathyroid, and thymus Dev Dyn 2009 238 503 513 19235715
- Krude H Schutz B Biebermann H von Moers A Schnabel D Neitzel H Tonnies H Weise D Lafferty A Schwarz S Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency J Clin Invest 2002 109 475 480 11854319 PMC150790
- Lania G Zhang Z Huynh T Caprio C Moon AM Vitelli F Baldini A Early thyroid development requires a Tbx1-Fgf8 pathway Dev Biol 2009 328 109 117 19389367 PMC2705775
- Longmire TA Ikonomou L Hawkins F Christodoulou C Cao Y Jean JC Kwok LW Mou H Rajagopal J Shen SS Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells Cell Stem Cell 2012 10 398 411 22482505 PMC3322392
- Ma R Latif R Davies TF Thyrotropin-independent induction of thyroid endoderm from embryonic stem cells by activin A Endocrinology 2009 150 1970 1975 19074581 PMC2659285
- Ma R Latif R Davies TF Thyroid follicle formation and thyroglobulin expression in multipotent endodermal stem cells Thyroid 2013 23 385 391 23360087 PMC3610443
- Ma R Latif R Davies TF Human embryonic stem cells form functional thyroid follicles Thyroid 2015 PMC4390159 25585054
- Mallette JM Anthony A Growth in culture of trypsin dissociated thyroid cells from adult rats Experimental cell research 1966 41 642 651 4952051
- Martin A Valentine M Unger P Lichtenstein C Schwartz AE Friedman EW Shultz LD Davies TF Preservation of functioning human thyroid organoids in the scid mouse: 1. System characterization The Journal of clinical endocrinology and metabolism 1993 77 305 310 8345031
- Murry CE Keller G Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development Cell 2008 132 661 680 18295582
- Parlato R Rosica A Rodriguez-Mallon A Affuso A Postiglione MP Arra C Mansouri A Kimura S Di LR De FM An integrated regulatory network controlling survival and migration in thyroid organogenesis DevBiol 2004 276 464 475 15581879
- Petryk A Anderson RM Jarcho MP Leaf I Carlson CS Klingensmith J Shawlot W O’Connor MB The mammalian twisted gastrulation gene functions in foregut and craniofacial development Dev Biol 2004 267 374 386 15013800
- Postiglione MP Parlato R Rodriguez-Mallon A Rosica A Mithbaokar P Maresca M Marians RC Davies TF Zannini MS De Felice M Role of the thyroid-stimulating hormone receptor signaling in development and differentiation of the thyroid gland Proc Natl Acad Sci U S A 2002 99 15462 15467 12432093 PMC137739
- Serls AE Doherty S Parvatiyar P Wells JM Deutsch GH Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung Development 2005 132 35 47 15576401
- Shifley ET Kenny AP Rankin SA Zorn AM Prolonged FGF signaling is necessary for lung and liver induction in Xenopus BMC Dev Biol 2012 12 27 22988910 PMC3514138
- Somers A Jean JC Sommer CA Omari A Ford CC Mills JA Ying L Sommer AG Jean JM Smith BW Generation of Transgene-Free Lung Disease-Specific Human iPS Cells Using a Single Excisable Lentiviral Stem Cell Cassette Stem Cells 2010 28 1728 1740 20715179 PMC3422663
- Trueba SS Auge J Mattei G Etchevers H Martinovic J Czernichow P Vekemans M Polak M Attie-Bitach T PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations The Journal of clinical endocrinology and metabolism 2005 90 455 462 15494458
- Vitelli F Taddei I Morishima M Meyers EN Lindsay EA Baldini A A genetic link between Tbx1 and fibroblast growth factor signaling Development 2002 129 4605 4611 12223416
- Wendl T Adzic D Schoenebeck JJ Scholpp S Brand M Yelon D Rohr KB Early developmental specification of the thyroid gland depends on han-expressing surrounding tissue and on FGF signals Development 2007 134 2871 2879 17611226
- Zuckier LS Dohan O Li Y Chang CJ Carrasco N Dadachova E Kinetics of perrhenate uptake and comparative biodistribution of perrhenate, pertechnetate, and iodide by NaI symporter-expressing tissues in vivo Journal of nuclear medicine: official publication, Society of Nuclear Medicine 2004 45 500 507 15001694
- Authors
- Kurmann, A. A., Serra, M., Hawkins, F., Rankin, S. A., Mori, M., Astapova, I., Ullas, S., Lin, S., Bilodeau, M., Rossant, J., Jean, J. C., Ikonomou, L., Deterding, R. R., Shannon, J. M., Zorn, A. M., Hollenberg, A. N., & Kotton, D. N.
- Affiliations
- Boston University (US)
- Cincinnati Children's Hospital Medical Center (US)
- Beth Israel Deaconess Medical Center (US)
- University of Toronto (CA)
- Children's Hospital Colorado (US)
- Corresponding author
- Hollenberg, Anthony N.
- Kotton, Darrell N.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 17
- Issue
- 5
- Pages
- 527-542
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC4666682
- OpenAlex
- W2174730790
- Cited by
- 204
- References
- 41
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 15 · 2023: 25 · 2022: 23 · 2021: 34 · 2020: 20 · 2019: 17 · 2018: 13 · 2017: 18 · 2016: 8 · 2015: 1
- FWCI
- 5.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (146612)
- Canadian Institutes of Health Research
- National Heart, Lung, and Blood Institute (R01HL114898, R01HL108678, U01HL110967, R01HL111574, R01HL122442, R01HL095993)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007516)
- 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
- thyroid regeneration, pluripotent stem cells, BMP signaling, FGF signaling, thyroid development, hypothyroidism, thyroid transplantation, thyroid hormone secretion, foregut endoderm, cell-based regenerative therapy
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Humans, Mice, Transgenic, Regeneration, Thyroid Gland, Xenopus, Pluripotent Stem Cells, Mice
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
