The hypothalamic-pituitary system is essential for maintaining life and for controlling systemic homeostasis, but is negatively affected by various diseases, leading to serious symptoms.

Embryonic stem (ES) cells differentiate into neuroectodermal progenitors when cultured as floating aggregates in serum-free conditions. Recently, our colleagues showed that strict removal of exogenous patterning factors during early differentiation steps induced efficient generation of rostral hypothalamic-like progenitors in mouse ES cell-derived neuroectodermal cells. The use of growth factor-free chemically defined medium was critical. The ES cell-derived hypothalamic-likeprogenitors generated rostral–dorsal hypothalamic neurons, especially magnocellular vasopressinergic neurons that release the hormone upon stimulation.

Subsequently, we reported an efficient self-formation of three-dimensional adenohypophysis tissues in aggregate culture of mouse ES cells. ES cells were stimulated to differentiate into non-neural head ectoderm and hypothalamic neuroectoderm in adjacent layers within the aggregate, and treated with Hedgehog signaling. Then, self-organization of Rathke’s pouch-like structures occurred at the interface of these two epithelia, as seen in vivo, and various endocrine cells including corticotrophs and somatotrophs were subsequently produced. The corticotrophs efficiently secreted ACTH in response to CRH, and, when grafted in vivo, these cells rescued the systemic glucocorticoid level in hypopituitary mice.

The present aims of our research are to prepare hypothalamic and pituitary tissues from human induced pluripotent stem (iPS) cells, and to establish effective transplantation techniques with clinical application as the goal. For replicating the complex and precise control of the hypothalamic-pituitary system, there are hopes for regenerative medicine using pluripotent cells.