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.
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Acknowledgements We thank G. Vassart, C. Blanpain and P. Vanderhaeghen for discussions and comments and V. Janssens for technical help. X.-H.L., A.M.D. and S.R. are supported in part by grants DK15070 and DK91016 from the National Institutes of Health. This work was supported by the Belgian Fonds de la Recherche Scientifique Medicale (FRSM3_4_557_08 and 3_4598_12), Action de Recherche Concertée de la Communauté Française de Belgique (ARC NuAUWB-08/13-ULB10), Fonds d’Encouragement à la Recherche and grants from the Belgian National Fund for Scientific Research (FNRS). F.A. and D.F.K. are FNRS and Fund for Research in the Industry and the Agriculture (FRIA) research fellows, R.O. is an FNRS Postdoctoral Researcher and S.C. is an FNRS Senior Research Associate.
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