Modeling Congenital Adrenal Hyperplasia and Testing Interventions for Adrenal Insufficiency Using Donor-Specific Reprogrammed Cells

Abstract

Summary: Adrenal insufficiency is managed by hormone replacement therapy, which is far from optimal; the ability to generate functional steroidogenic cells would offer a unique opportunity for a curative approach to restoring the complex feedback regulation of the hypothalamic-pituitary-adrenal axis. Here, we generated human induced steroidogenic cells (hiSCs) from fibroblasts, blood-, and urine-derived cells through forced expression of steroidogenic factor-1 and activation of the PKA and LHRH pathways. hiSCs had ultrastructural features resembling steroid-secreting cells, expressed steroidogenic enzymes, and secreted steroid hormones in response to stimuli. hiSCs were viable when transplanted into the mouse kidney capsule and intra-adrenal. Importantly, the hypocortisolism of hiSCs derived from patients with adrenal insufficiency due to congenital adrenal hyperplasia was rescued by expressing the wild-type version of the defective disease-causing enzymes. Our study provides an effective tool with many potential applications for studying adrenal pathobiology in a personalized manner and opens venues for the development of precision therapies. : Ruiz-Babot et al. generate functional human steroidogenic cells (hiSCs), which are responsive to both pharmacological and physiological stimuli. Moreover, the hypocortisolism in hiSCs derived from patients with congenital adrenal hyperplasia is restored to normal through the incorporation of the wild-type version of the defective disease-causing enzymes. Keywords: steroidogenic cells, adrenal cortex, steroidogenic factor 1, NR5A1, reprogramming, urine-derived stem cells, adrenal insufficiency, congenital adrenal hyperplasia, disease modeling, transplantation