Background: This study aimed to develop an innovative therapeutic approach for hypopituitarism, disorder characterized by various hormonal imbalances leading to diverse symptoms. In particular, the potential life-threatening adrenal crisis caused by lowered ACTH levels is critical. Although the current treatment involves hormone replacement therapy (HRT), its inability to adequately mimic the body’s finely tuned hormone fluctuations contributes to a higher risk of sudden death compared with healthy individuals. The objective is to create pituitary hormone-producing cells that respond to the environment similar to the human body, offering a more effective treatment than current HRT.

Methods: In the clinical application of human pluripotent stem cell (hPSC)-derived pituitary cells, our research group achieved a 100% success rate in generating pituitary– hypothalamus organoids (POs), including ACTH-producing cells from human embryonic stem cells (hESCs). To demonstrate proof of concept for these products, we transplanted pituitary organoids (POs), generated from human embryonic stem (ES) cells using the aforementioned method, into the subcutaneous tissue of immunodeficient SCID mice with hypophysectomy-induced hypopituitarism, and evaluated their effects. Subsequently, to assess the efficacy in a large animal model, we established a hypopituitarism model in cynomolgus monkeys and performed subcutaneous transplantation of POs using an immunosuppressive protocol commonly employed in clinical human islet transplantation.

Results: In mice, the transplanted POs survived for over six months and significantly improved plasma ACTH levels. The transplantation group exhibited improved survival compared to the sham-operated group. In cynomolgus monkeys, the transplanted POs remained functional for one month, led to an increase in plasma ACTH levels, and demonstrated histological engraftment at three months.

Conclusion: After demonstrating therapeutic efficacy in rodents, the transplantation of POs into primates also showed short-term effects. Our future research agenda includes the accumulation of comprehensive non-clinical data to support the design of human clinical trials. This will involve studies utilizing large animal models to optimize transplantation techniques, assess immunosuppressive and adjunctive therapies, and validate safety and efficacy parameters. In parallel, we aim to establish a scalable manufacturing platform utilizing clinical-grade iPSCs, thereby laying the foundation for the eventual clinical realization of pituitary cell-based transplantation therapies.