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

67 Pages Posted: 11 Apr 2018 Sneak Peek Status: Published

See all articles by Gerard Ruiz-Babot

Gerard Ruiz-Babot

Queen Mary University of London - Centre for Endocrinology

Mariya Balyura

Dresden University of Technology - Department of Internal Medicine III

Irene Hadjidemetriou

Queen Mary University of London - Centre for Endocrinology

Sharon J. Ajodha

Queen Mary University of London - Centre for Endocrinology

David R. Taylor

NHS Foundation Trust - Department of Clinical Biochemistry

Lea Ghataore

NHS Foundation Trust - Department of Clinical Biochemistry

Norman F. Taylor

NHS Foundation Trust - Department of Clinical Biochemistry

Undine Schubert

Dresden University of Technology - Department of Internal Medicine III

Helen L. Storr

Queen Mary University of London - Centre for Endocrinology

Maralyn R. Druce

Queen Mary University of London - Centre for Endocrinology

Evelien F. Gevers

Queen Mary University of London - Centre for Endocrinology

William M. Drake

Queen Mary University of London - Centre for Endocrinology

Umasuthan Srirangalingam

Government of the United Kingdom - Department of Endocrinology

Gerard S. Conway

Government of the United Kingdom - Department of Endocrinology

Peter J. King

Queen Mary University of London - Centre for Endocrinology

Louise A. Metherell

Queen Mary University of London - Centre for Endocrinology

Stefan R. Bornstein

Dresden University of Technology - Department of Internal Medicine III; Dresden University of Technology - Paul Langerhans Institute Dresden (PLID); University of London - Diabetes and Nutritional Sciences; German Center for Diabetes Research

Leonardo Guasti

Queen Mary University of London - Centre for Endocrinology

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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.

Suggested Citation

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 is a paper under consideration at Cell Press and has not been peer-reviewed.

Gerard Ruiz-Babot

Queen Mary University of London - Centre for Endocrinology

London, EC1M 6BQ
United Kingdom

Mariya Balyura

Dresden University of Technology - Department of Internal Medicine III

Dresden, 01307
Germany

Irene Hadjidemetriou

Queen Mary University of London - Centre for Endocrinology

London, EC1M 6BQ
United Kingdom

Sharon J. Ajodha

Queen Mary University of London - Centre for Endocrinology

London, EC1M 6BQ
United Kingdom

David R. Taylor

NHS Foundation Trust - Department of Clinical Biochemistry

London, SE5 9RS
United Kingdom

Lea Ghataore

NHS Foundation Trust - Department of Clinical Biochemistry

London, SE5 9RS
United Kingdom

Norman F. Taylor

NHS Foundation Trust - Department of Clinical Biochemistry

London, SE5 9RS
United Kingdom

Undine Schubert

Dresden University of Technology - Department of Internal Medicine III

Dresden, 01307
Germany

Helen L. Storr

Queen Mary University of London - Centre for Endocrinology

London, EC1M 6BQ
United Kingdom

Maralyn R. Druce

Queen Mary University of London - Centre for Endocrinology

London, EC1M 6BQ
United Kingdom

Evelien F. Gevers

Queen Mary University of London - Centre for Endocrinology

London, EC1M 6BQ
United Kingdom

William M. Drake

Queen Mary University of London - Centre for Endocrinology

London, EC1M 6BQ
United Kingdom

Umasuthan Srirangalingam

Government of the United Kingdom - Department of Endocrinology

250 Euston Road
3rd Floor Central Wing
London, NW1 2PG
United Kingdom

Gerard S. Conway

Government of the United Kingdom - Department of Endocrinology

250 Euston Road
3rd Floor Central Wing
London, NW1 2PG
United Kingdom

Peter J. King

Queen Mary University of London - Centre for Endocrinology

London, EC1M 6BQ
United Kingdom

Louise A. Metherell

Queen Mary University of London - Centre for Endocrinology

London, EC1M 6BQ
United Kingdom

Stefan R. Bornstein

Dresden University of Technology - Department of Internal Medicine III

Dresden, 01307
Germany

Dresden University of Technology - Paul Langerhans Institute Dresden (PLID)

Einsteinstrasse 3
Dresden, 01062
Germany

University of London - Diabetes and Nutritional Sciences

United Kingdom

German Center for Diabetes Research

Germany

Leonardo Guasti (Contact Author)

Queen Mary University of London - Centre for Endocrinology ( email )

London, EC1M 6BQ
United Kingdom

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