Modeling Congenital Adrenal Hyperplasia and Testing Interventions for Adrenal Insufficiency Using Donor-Specific Reprogrammed Cells
Gerard Ruiz-Babot,
Mariya Balyura,
Irene Hadjidemetriou,
Sharon J. Ajodha,
David R. Taylor,
Lea Ghataore,
Norman F. Taylor,
Undine Schubert,
Christian G. Ziegler,
Helen L. Storr,
Maralyn R. Druce,
Evelien F. Gevers,
William M. Drake,
Umasuthan Srirangalingam,
Gerard S. Conway,
Peter J. King,
Louise A. Metherell,
Stefan R. Bornstein,
Leonardo Guasti
Affiliations
Gerard Ruiz-Babot
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK
Mariya Balyura
University Hospital Carl Gustav Carus, Department of Medicine III, Technische Universität Dresden, 01307 Dresden, Germany
Irene Hadjidemetriou
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK
Sharon J. Ajodha
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK
David R. Taylor
Department of Clinical Biochemistry, King’s College Hospital NHS Foundation Trust, Denmark Hill, SE5 9RS London, UK
Lea Ghataore
Department of Clinical Biochemistry, King’s College Hospital NHS Foundation Trust, Denmark Hill, SE5 9RS London, UK
Norman F. Taylor
Department of Clinical Biochemistry, King’s College Hospital NHS Foundation Trust, Denmark Hill, SE5 9RS London, UK
Undine Schubert
University Hospital Carl Gustav Carus, Department of Medicine III, Technische Universität Dresden, 01307 Dresden, Germany
Christian G. Ziegler
University Hospital Carl Gustav Carus, Department of Medicine III, Technische Universität Dresden, 01307 Dresden, Germany
Helen L. Storr
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK
Maralyn R. Druce
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK
Evelien F. Gevers
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK
William M. Drake
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK
Umasuthan Srirangalingam
Department of Endocrinology, University College London Hospitals, NW1 2PG London, UK
Gerard S. Conway
Department of Endocrinology, University College London Hospitals, NW1 2PG London, UK
Peter J. King
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK
Louise A. Metherell
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK
Stefan R. Bornstein
University Hospital Carl Gustav Carus, Department of Medicine III, Technische Universität Dresden, 01307 Dresden, Germany; Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU Dresden Faculty of Medicine, Technische Universität Dresden, DZD-German Centre for Diabetes Research, 01307 Dresden, Germany; Center for Regenerative Therapies, Technische Universität Dresden, 01307 Dresden, Germany; Diabetes and Nutritional Sciences Division, King’s College London, WC2R 2LS London, UK
Leonardo Guasti
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK; Corresponding author
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
