{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T13:58:28Z","timestamp":1768831108797,"version":"3.49.0"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T00:00:00Z","timestamp":1625184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>The synergistic activation of transcription factors can lead to thyroid progenitor cell speciation. We have previously shown <jats:italic>in vitro<\/jats:italic> that mouse or human stem cells, expressing the transcription factors NKx2-1 and Pax8, can differentiate into thyroid neo-follicular structures (TFS). We now show that syngeneic mouse TFS when implanted into hypothyroid TSH receptor knockout (TSHR-KO) mice can ameliorate the hypothyroid state for an extended period. ES cells derived from heterozygous TSHR-KO blastocysts were stably transfected with Nkx2-1-GFP and Pax8-mcherry constructs and purified into 91.8% double positive cells by flow cytometry. After 5 days of activin A treatment these double positive cells were then induced to differentiate into neo-follicles in Matrigel for 21 days in the presence of 500\u03bcU\/mL of TSH. Differentiated TFS expressing thyroglobulin mRNA were implanted under the kidney capsule of 4-6 weeks old TSHR-KO mice (n=5) as well as hind limb muscle (n=2) and anterior chamber of one eye (n=2). Five of the mice tested after 4 weeks were all rendered euthyroid and all mice remained euthyroid at 20 weeks post implantation. The serum T4 fully recovered (pre-bleed 0.62 \u00b1 0.03 to 8.40 \u00b1 0.57 \u00b5g\/dL) and the previously elevated TSH became normal or suppressed (pre-bleed 391 \u00b1 7.6 to 4.34 \u00b1 1.25 ng\/dL) at the end of the 20 week observation period. The final histology obtained from the implanted kidney tissues showed only rudimentary thyroid follicular structures but which stained positive for thyroglobulin expression. The presence of only rudimentary structures at the site of implant on these extended animals suggested possible migration of cells from the site of implant or an inability of TFCs to maintain proper follicular morphology in these external sites for extended periods. However, there were no signs of tumor formation and no immune infiltration. These preliminary studies show that TSHR-KO mice are a useful model for orthotropic implantation of functional thyroid cells without the need for thyroidectomy, radioiodine ablation or anti thyroid drug control of thyroid function. This approach is also proof of principle that thyroid cells derived from mouse ES cells are capable of surviving as functional neo-follicles <jats:italic>in vivo<\/jats:italic> for an extended period of 20 weeks.<\/jats:p>","DOI":"10.3389\/fendo.2021.706101","type":"journal-article","created":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T08:44:05Z","timestamp":1625215445000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Long Term Rescue of the TSH Receptor Knock-Out Mouse \u2013 Thyroid Stem Cell Transplantation Restores Thyroid Function"],"prefix":"10.3389","volume":"12","author":[{"given":"Rauf","family":"Latif","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Risheng","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Syed A.","family":"Morshed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bengu","family":"Tokat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terry F.","family":"Davies","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.242322099","article-title":"Defining Thyrotropin-Dependent and -Independent Steps of Thyroid Hormone Synthesis by Using Thyrotropin Receptor-Null Mice","volume":"99","author":"Marians","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2012.0644","article-title":"Thyroid Follicle Formation and Thyroglobulin Expression in Multipotent Endodermal Stem Cells","volume":"23","author":"Ma","year":"2013","journal-title":"Thyroid"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2015.00056","article-title":"Thyroid Cell Differentiation From Murine Induced Pluripotent Stem Cells","volume":"6","author":"Ma","year":"2015","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2014.0537","article-title":"Human Embryonic Stem Cells Form Functional Thyroid Follicles","volume":"25","author":"Ma","year":"2015","journal-title":"Thyroid"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005-1239","article-title":"Directed Differentiation of Mouse Embryonic Stem Cells Into Thyroid Follicular Cells","volume":"147","author":"Arufe","year":"2006","journal-title":"Endocrinology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)98913-1","article-title":"Folding and Assembly of Newly Synthesized Thyroglobulin Occurs in a pre-Golgi Compartment","volume":"266","author":"Kim","year":"1991","journal-title":"J Biol Chem"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1385\/1-59745-036-7:249","article-title":"Derivation and Characterization of Thyrocyte-Like Cells From Embryonic Stem Cells In Vitro","volume":"330","author":"Lin","year":"2006","journal-title":"Methods Mol Biol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.77.2.8345031","article-title":"Preservation of Functioning Human Thyroid Organoids in the Scid Mouse: 1. System Characterization","volume":"77","author":"Martin","year":"1993","journal-title":"J Clin Endocrinol Metab"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2020.0930","article-title":"The Transient Human Thyroid Progenitor Cell: Examining the Thyroid Continuum From Stem Cell to Follicular Cell","author":"Davies","year":"2021","journal-title":"Thyroid"},{"key":"B10","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1038\/nature11525","article-title":"Generation of Functional Thyroid From Embryonic Stem Cells","volume":"491","author":"Antonica","year":"2012","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.242328999","article-title":"Role of the Thyroid-Stimulating Hormone Receptor Signaling in Development and Differentiation of the Thyroid Gland","volume":"99","author":"Postiglione","year":"2002","journal-title":"Proc\u00a0Natl Acad Sci USA"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00771-2","article-title":"TSH Is a Negative Regulator of Skeletal Remodeling","volume":"115","author":"Abe","year":"2003","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI63948","article-title":"Hyperthyroid-Associated Osteoporosis Is Exacerbated by the Loss of TSH Signaling","volume":"122","author":"Baliram","year":"2012","journal-title":"J Clin Invest"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-17-0680","article-title":"Actions of Pituitary Hormones Beyond Traditional Targets","volume":"237","author":"Zaidi","year":"2018","journal-title":"J Endocrinol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1210\/en.2003-1384","article-title":"Thyrotropin Receptor Knockout Mice: Studies on Immunological Tolerance to a Major Thyroid Autoantigen","volume":"145","author":"Pichurin","year":"2004","journal-title":"Endocrinology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1210\/er.2013-1055","article-title":"Breaking Tolerance to Thyroid Antigens: Changing Concepts in Thyroid Autoimmunity","volume":"35","author":"McLachlan","year":"2014","journal-title":"Endocr Rev"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2000.10.481","article-title":"Thyroid Organoid Formation in Simulated Microgravity: Influence of Keratinocyte Growth Factor","volume":"10","author":"Martin","year":"2000","journal-title":"Thyroid"},{"key":"B18","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/978-1-4939-6949-4_7","article-title":"Generation of Functional Thyroid Tissue Using 3D-Based Culture of Embryonic Stem Cells","volume":"1597","author":"Antonica","year":"2017","journal-title":"Methods Mol Biol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2015.09.004","article-title":"Regeneration of Thyroid Function by Transplantation of Differentiated Pluripotent Stem Cells","volume":"17","author":"Kurmann","year":"2015","journal-title":"Cell Stem Cell"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-016-3883-x","article-title":"The Anterior Chamber of the Eye Is a Transplantation Site That Supports and Enables Visualisation of Beta Cell Development in Mice","volume":"59","author":"Ali","year":"2016","journal-title":"Diabetologia"},{"key":"B21","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1007\/BF03086124","article-title":"Cell Transplantation for Cardiac Regeneration: Where do We Stand","volume":"16","author":"van den Bos","year":"2008","journal-title":"Neth Heart J"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1006\/nimg.2002.1194","article-title":"Tracking Transplanted Stem Cell Migration Using Bifunctional, Contrast Agent-Enhanced, Magnetic Resonance Imaging","volume":"17","author":"Modo","year":"2002","journal-title":"Neuroimage"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.706101\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T08:44:07Z","timestamp":1625215447000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.706101\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,2]]},"references-count":22,"alternative-id":["10.3389\/fendo.2021.706101"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.706101","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,2]]},"article-number":"706101"}}