Making pituitary hormone-producing cells in a dish [Review]

The hypothalamic-pituitary system is essential for maintaining life and controlling systemic homeostasis. The functional disorder makes patients suffer from various symptoms all their lives. Pluripotent stem cells, such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, differentiate into neuroectodermal progenitors when cultured as floating aggregates under serum-free conditions. Recent results have shown that strict removal of exogenous patterning factors during the early differentiation period induces rostral hypothalamic-like progenitors from mouse ES cells. The use of growth factor-free, chemically defined medium was critical for this induction. The ES cell-derived hypothalamic-like progenitors generated rostral-dorsal hypothalamic neurons, in particular magnocellular vasopressinergic neurons. We subsequently reported self-formation of adenohypophysis in three-dimensional floating cultures of mouse ES cells. The ES cell aggregates were stimulated to differentiate into both non-neural head ectoderm and hypothalamic neuroectoderm in adjacent layers. Self-organization of Rathke's pouch-like structures occurred at the interface of the two epithelia in vitro. Various pituitary endocrine cells including corticotrophs and somatotrophs were subsequently produced from the Rathke's pouch-like structures. The induced corticotrophs efficiently secreted ACTH in response to CRH. Furthermore, when engrafted in vivo, these cells rescued systemic glucocorticoid levels in hypopituitary mice. Our latest study aimed to prepare hypothalamic and pituitary tissues from human pluripotent stem cells. We succeeded in establishing the differentiation method using human ES/iPS cells. The culture method is characterized by replication of stepwise embryonic differentiation. Therefore, these methods could potentially be used as developmental and disease models, as well as for future regenerative medicine.