Dresden University of Technology - Department of Internal Medicine III; Dresden University of Technology - Paul Langerhans Institute Dresden (PLID); King’s College London - Diabetes and Nutritional Sciences; German Center for Diabetes Research
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.
Ruiz-Babot, Gerard and Balyura, Mariya and Hadjidemetriou, Irene and Ajodha, Sharon J. and Taylor, David R. and Ghataore, Lea and Taylor, Norman F. and Schubert, Undine and Storr, Helen L. and Druce, Maralyn R. and Gevers, Evelien F. and Drake, William M. and Srirangalingam, Umasuthan and Conway, Gerard S. and King, Peter J. and Metherell, Louise A. and Bornstein, Stefan R. and Guasti, Leonardo, Modeling Congenital Adrenal Hyperplasia and Testing Interventions for Adrenal Insufficiency Using Donor-Specific Reprogrammed Cells (2018). Available at SSRN: https://ssrn.com/abstract=3155848 or http://dx.doi.org/10.2139/ssrn.3155848
This version of the paper has not been formally peer reviewed.
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