Functional analysis of adrenocorticotropic-hormone-producing pituitary cells derived from human pluripotent stem cells in murine and primate models of hypopituitarism.

BACKGROUND: Hypopituitarism has a prevalence of approximately 45.5 cases per 100,000 population, is therefore not a rare condition. Hypopituitarism does not resolve spontaneously and is designated as an intractable disease. In particular, deficiency of adrenocorticotropic hormone (ACTH) can result in adrenal insufficiency and life-threatening crises. The current standard of care is hormone replacement therapy; however, precise adjustment to match the physiological variations of hormone demand, such as circadian rhythm and stress responses, is often difficult. Consequently, hypopituitarism patients face a risk of sudden death higher than that in healthy individuals. Our goal is to generate pituitary hormone-producing cells capable of responding to environmental cues, and thereby to provide a novel therapy with physiological responsiveness and assured safety.

METHODS: We previously established a clinically relevant protocol for efficiently generating pituitary-hypothalamus organoids, containing ACTH-producing cells, from human pluripotent stem cells (hPSCs). To provide proof of concept for their therapeutic use as pituitary cell preparations, we transplanted human embryonic-stem-cell-derived pituitary-hypothalamus organoids beneath the subcutaneous tissue of hypopituitary severe combined immunodeficiency mice and evaluated their effects. We next created a hypopituitary cynomolgus monkey model and performed subcutaneous transplantation of pituitary-hypothalamus organoids under an immunosuppressive regimen adapted from human clinical islet-transplantation protocols.

RESULTS: In mice, transplanted pituitary-hypothalamus organoids survived for more than 6 mo, significantly improved circulating ACTH concentrations, and prolonged survival beyond that of sham-operated mice. In a cynomolgus monkey, transplanted organoids functioned for 6 w and increased circulating ACTH concentrations.

CONCLUSIONS: To our knowledge, no previous study in primates has demonstrated efficacious pituitary cell transplantation, whether derived from fetal pituitary, xenogeneic pituitary, or PSCs. Future priorities include the acquisition of comprehensive non-clinical data to inform design of first-in-human clinical trials; optimisation of transplantation techniques; evaluation of immunosuppressive and adjunctive therapies; and assessment of safety and efficacy parameters. In parallel, the development of scalable manufacturing platforms utilising clinical-grade induced PSCs will be essential to establish the foundation for the eventual clinical application of pituitary cell transplantation therapy.