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

Abstract 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.