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The pituitary is a major hormone center that secretes systemic hormones responding to hypothalamus-derived-releasing hormones. Previously, we reported the independent pituitary induction and hypothalamic differentiation of human embryonic stem cells (ESCs). Here, a functional hypothalamic-pituitary unit is generated using human induced pluripotent stem (iPS) cells in vitro. The adrenocorticotropic hormone (ACTH) secretion capacity of the induced pituitary reached a comparable level to that of adult mouse pituitary because of the simultaneous maturation with hypothalamic neurons within the same aggregates. Corticotropin-releasing hormone (CRH) from the hypothalamic area regulates ACTH cells similarly to our hypothalamic-pituitary axis. Our induced hypothalamic-pituitary units respond to environmental hypoglycemic condition in vitro, which mimics a life-threatening situation in vivo, through the CRH-ACTH pathway, and succeed in increasing ACTH secretion. Thus, we generated powerful hybrid organoids by recapitulating hypothalamic-pituitary development, showing autonomous maturation on the basis of interactions between developing tissues.
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•Hypothalamic-pituitary functional units can be generated from 3D-cultured human iPS cells•Maturation of induced pituitary through simultaneous culture with hypothalamic neurons•ACTH secretion ability of induced pituitary is comparable with adult mice•Induced pituitary cells respond to low-glucose stimulation through the CRH-ACTH pathway
Kasai et al. generate a functional hypothalamic-pituitary unit using human iPS cells. The ACTH secretion capacity of induced pituitary cells reaches the same level as adult mice anterior pituitary cells. The hypothalamic-pituitary unit responds to environmental stimulation such as low glucose through the CRH-ACTH pathway.