Abstract
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 invitro. 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 invitro, which mimics a life-threatening situation invivo, 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.
Highlights
Several studies have reported methods to differentiate human pluripotent stem cells into anterior pituitary in vitro (Ozone et al, 2016; Dincer et al, 2013; Zimmer et al, 2016)
We have succeeded in generating a functional anterior pituitary from mouse and human embryonic stem cells (ESCs) (Ozone et al, 2016; Suga et al, 2011)
We examined five factors: the initial number of cells per well, the concentration of KSR added to growth factor-free chemically defined medium, bone morphogenetic protein 4 (BMP4) concentration, smoothened agonist (SAG; for activation of the Sonic hedgehog pathway) concentration, and the timing of BMP4 addition (Figure S1A)
Summary
Several studies have reported methods to differentiate human pluripotent stem cells into anterior pituitary in vitro (Ozone et al, 2016; Dincer et al, 2013; Zimmer et al, 2016). We have succeeded in generating a functional anterior pituitary from mouse and human embryonic stem cells (ESCs) (Ozone et al, 2016; Suga et al, 2011). Our method places emphasis on reproducing developmental processes using three-dimensional (3D) culture. We used 3D culture called SFEBq (serum-free floating culture of embryoid body-like aggregates with quick reaggregation) (Eiraku et al, 2008), which induces ectodermal tissue with high quality
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