Differentiation of pluripotent stem cells into hypothalamic and pituitary cells

Abstract

The hypothalamic-pituitary system is essential to maintain life and control systemic homeostasis, but it is negatively affected by various diseases, leading to serious symptoms. Embryonic stem (ES) cells differentiate into neuroectodermal progenitors when cultured as floating aggregates under serum-free conditions. Recently, our colleagues have shown that strict removal of exogenous patterning factors during early differentiation steps induced efficient generation of rostral hypothalamic-like progenitors from mouse ES cell-derived neuroectodermal 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, especially magnocellular vasopressinergic neurons that release the hormone upon stimulation. Subsequently, we reported efficient self-formation of 3-dimensional adenohypophysis tissues in aggregate cultures of mouse ES cells. The ES cells were stimulated to differentiate into nonneural head ectoderm and hypothalamic neuroectoderm in adjacent layers within the aggregate and then treated with hedgehog. Self-organization of Rathke's pouch-like structures occurred at the interface of the two epithelia, as observed in vivo, and various endocrine cells including corticotrophs and somatotrophs were subsequently produced. The corticotrophs efficiently secreted adrenocorticotropic hormone in response to corticotropin-releasing hormone. Furthermore, when engrafted in vivo, these cells rescued the systemic glucocorticoid level in hypopituitary mice. Our present research aims are to prepare hypothalamic and pituitary tissues from human induced pluripotent stem cells and establish effective transplantation techniques with clinical applications. To replicate the complex and precise control of the hypothalamic-pituitary system, regenerative medicine using pluripotent cells may be a hopeful option.