Reconstitution of Adrenal 3D Structure from Human Pluripotent Stem Cells: A Challenge toward Regenerative Medicine for Adrenal Insufficiency

The adrenal glands, crucial endocrine organs located above the kidneys, produce steroids essential for maintaining body homeostasis. Steroid production must be tightly regulated by the hypothalamic-pituitary-adrenal axis, which responds to stress levels through feedback mechanisms involving CRH, ACTH, and cortisol, thereby adjusting to changing stress levels. Patients with adrenal insufficiency require lifelong steroid replacement therapy. The difficulty in controlling physiological steroid levels results in possible life-threatening side effects. Novel treatments for adrenal insufficiency are thus sought. We established human iPSC-derived adrenal organoids that maintain a physiological adrenal zonal structure, comprising capsular-like cells, definitive zone-like cells, transitional zone-like cells, and fetal zone-like cells, as well as ACTH-dependent steroid production, demonstrating promise for responsive steroid production in response to stress levels. Additionally, the organoids contain an adrenal stem cell population, which ensures long-term therapeutic effects. These features of the adrenal organoids show the potential applications in regenerative therapies for adrenal insufficiency. Current efforts focus on developing treatment models using adrenal organoids for adrenal insufficiency in immunodeficient mice.