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. Transient overexpression of the transcription factors NKX2-1 and PAX8 in a murine cell model is shown to direct the differentiation of embryonic stem cells towards a thyroid follicular cell lineage; the resulting three-dimensional thyroid follicles created by subsequent thyrotropin treatment show hallmarks of thyroid function in vitro and rescue thyroid function in vivo when transplanted into athyroid mice, adding to our understanding of the molecular mechanisms underlying thyroid development. Sabine Costagliola and colleagues report a protocol that converts mouse embryonic stem cells into functional thyroid follicles in vitro. Overexpression of the transcription factors NKX2.1 and PAX8 directs differentiation towards thyroid follicular cells, which undergo self-assembly when treated with thyrotropin. The resulting three-dimensional thyroid follicles show hallmarks of thyroid function in vitro, and can rescue multiple symptoms when transplanted into athyroid mice. This work not only adds to our understanding of the molecular mechanism behind thyroid development, but also paves the way for regenerative medicine to treat congenital hypothyroidism, the most common congenital endocrine disease in humans.