ABSTRACT
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.
Subject(s)
Cell Differentiation , Embryonic Stem Cells/cytology , Thyroid Gland/cytology , Thyroid Gland/physiology , Animals , Disease Models, Animal , Embryonic Stem Cells/metabolism , Female , Humans , Hypothyroidism/pathology , Hypothyroidism/surgery , Hypothyroidism/therapy , Mice , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , PAX8 Transcription Factor , Paired Box Transcription Factors/genetics , Paired Box Transcription Factors/metabolism , Thyroid Gland/anatomy & histology , Thyroid Gland/drug effects , Thyroid Gland/transplantation , Thyroid Nuclear Factor 1 , Thyrotropin/blood , Thyrotropin/pharmacology , Thyroxine/blood , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Monocarboxylate transporter 8 acts as a specific cell membrane transporter for thyroxine and especially triiodothyronine into target cells. It is expressed in brain neurons and in many other tissues. The monocarboxylate transporter 8 gene resides on chromosome Xq13.2. An 11-month-old male infant was referred because of severe hypotonia from early life and global developmental delay. Thyroid-function tests showed normal thyrotropin levels and the characteristic for the disorder, including high serum triiodothyronine and low thyroxine concentrations. Molecular analysis of the monocarboxylate transporter 8 gene showed that the patient was hemizygous for a novel missense mutation P537L. This case highlights the importance of determining thyroid hormone levels, especially triiodothyronine, in infants with severe neonatal hypotonia.
