Modeling congenital adrenal hyperplasia and testing interventions for adrenal insufficiency using donor- specific reprogrammed cells.
MetadataShow full item record
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.
AuthorsGUASTI, L; Ruiz-Babot, G; Balyura, M; HADJIDEMETRIOU, I; AJODHA, S; Taylor, D; Ghataore, L; Taylor, N; Schubert, U; Ziegler, C; STORR, HL; DRUCE, MR; GEVERS, EF; DRAKE, WM; Srirangalingam, U; Conway, G; KING, P; METHERELL, LA; Bornstein, S
- Endocrinology 
Showing items related by title, author, creator and subject.
Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Meimaridou, E; Kowalczyk, J; Guasti, L; Hughes, CR; Wagner, F; Frommolt, P; Nürnberg, P; Mann, NP; Banerjee, R; Saka, HN;... (Nature Publications, 2012-05-27)Using targeted exome sequencing, we identified mutations in NNT, an antioxidant defense gene, in individuals with familial glucocorticoid deficiency. In mice with Nnt loss, higher levels of adrenocortical cell apoptosis ...
Common genetic variants of the human steroid 21-hydroxylase gene (CYP21A2) are related to differences in circulating hormone levels. Doleschall, M; Szabó, JA; Pázmándi, J; Szilágyi, Á; Koncz, K; Farkas, H; Tóth, M; Igaz, P; Gláz, E; Prohászka, Z;... (2014-09-11)PURPOSE: Systematic evaluation of the potential relationship between the common genetic variants of CYP21A2 and hormone levels. METHODS: The relationships of CYP21A2 intron 2 polymorphisms and haplotypes with diverse ...
Prasad, R; Kowalczyk, JC; Meimaridou, E; Storr, HL; Metherell, LA (Bioscientifica, 2014-03-12)Maintenance of redox balance is essential for normal cellular functions. Any perturbation in this balance due to increased reactive oxygen species (ROS) leads to oxidative stress and may lead to cell dysfunction/damage/death. ...