Abstract
Anterior pituitary is critical for endocrine systems. Its hormonal responses to positive and negative regulators are indispensable for homeostasis. For this reason, generating human anterior pituitary tissue that retains regulatory hormonal control in vitro is an important step for the development of cell transplantation therapy for pituitary diseases. Here we achieve this by recapitulating mouse pituitary development using human embryonic stem cells. We find that anterior pituitary self-forms in vitro following the co-induction of hypothalamic and oral ectoderm. The juxtaposition of these tissues facilitated the formation of pituitary placode, which subsequently differentiated into pituitary hormone-producing cells. They responded normally to both releasing and feedback signals. In addition, after transplantation into hypopituitary mice, the in vitro-generated corticotrophs rescued physical activity levels and survival of the hosts. Thus, we report a useful methodology for the production of regulator-responsive human pituitary tissue that may benefit future studies in regenerative medicine.
Highlights
Anterior pituitary is critical for endocrine systems
Previous studies[11] using mouse ES cells showed that hypothalamic NE can be co-induced with non-neural ectoderm within the same SFEBq aggregates by high-density cell plating and optimized culture media
Plasma corticosterone levels were significantly higher in the grafted group (Fig. 4e), and basal levels of adrenocorticotropic hormone (ACTH) and corticosterone were increased (Fig. 4f,g). (Before these experiments, we demonstrated that human ACTH had the ability to induce a substantial elevation of blood ACTH levels in wild-type severe combined immunodeficient (SCID) mice; Supplementary Fig. 4i.) These results indicated that ACTH from the grafts sufficiently stimulated the host adrenal glands and were functional within the host’s hormonal system
Summary
Its hormonal responses to positive and negative regulators are indispensable for homeostasis For this reason, generating human anterior pituitary tissue that retains regulatory hormonal control in vitro is an important step for the development of cell transplantation therapy for pituitary diseases. The ability to create human pituitary tissue, which can respond to the surrounding environment, amenable to effective curative therapies for pituitary dysfunction would be a huge advance for regenerative medicine Towards this aim, Dincer et al.[3] reported the generation of pituitary hormone-producing cells from human pluripotent stem cells, yet whether these cells were responsive (that is, could respond to their regulatory cues) was not determined. The hESC-derived pituitary progenitors differentiated into mature hormone-producing cells, such as corticotrophs and somatotrophs They secreted ACTH and GH, respectively, in response to positive and negative regulatory signals. HESC-derived pituitary tissues shown here provide a platform for therapeutic application and disease modelling
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