1. Modeling Congenital Adrenal Hyperplasia and Testing Interventions for Adrenal Insufficiency Using Donor-Specific Reprogrammed Cells
- Author
-
Maralyn Druce, Evelien F. Gevers, Mariya Balyura, Peter J. King, Gerard Ruiz-Babot, Leonardo Guasti, Irene Hadjidemetriou, Sharon Ajodha, Umasuthan Srirangalingam, David R Taylor, Lea Ghataore, Stefan R. Bornstein, Gerard S. Conway, Louise A. Metherell, William Drake, Helen L Storr, Undine Schubert, and Norman F. Taylor
- Subjects
chemistry.chemical_classification ,business.industry ,medicine.medical_treatment ,medicine.disease ,Feedback regulation ,Steroid ,Steroidogenic enzymes ,Enzyme ,chemistry ,Adrenal insufficiency ,Cancer research ,Medicine ,Congenital adrenal hyperplasia ,Hormone replacement therapy ,business ,Hormone - Abstract
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 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 PKA and LHRH pathways. hiSCs had ultrastructural features resembling steroid-secreting cells, expressed steroidogenic enzymes and secreted steroid hormones in response to stimuli. hiSCs successfully engrafted into the mouse kidney capsule and underwent intra-adrenal differentiation. 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 to study adrenal pathobiology in a personalized manner and opens venues for the development of precision therapies.
- Published
- 2018
- Full Text
- View/download PDF