Generation of functional thyroid from embryonic stem cells.
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.
Institute of Interdisciplinary Research in Molecular Human Biology (IRIBHM), Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
Francesco
F
Antonica
Dominika Figini
DF
Kasprzyk
Robert
R
Opitz
Michelina
M
Iacovino
Xiao-Hui
XH
Liao
Alexandra Mihaela
AM
Dumitrescu
Samuel
S
Refetoff
Kathelijne
K
Peremans
Mario
M
Manto
Michael
M
Kyba
Sabine
S
Costagliola
D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000473:pathology / Q000601:surgery / Q000628:therapy; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D013961:Thyroid Gland / Q000033:anatomy & histology / Q000166:cytology* / Q000187:drug effects / Q000502:physiology* / Q000637:transplantation; D000074482:Thyroid Nuclear Factor 1; D013972:Thyrotropin / Q000097:blood / Q000494:pharmacology; D013974:Thyroxine / Q000097:blood; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D013972:Thyrotropin; D013974:Thyroxine