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Endocrine Abstracts (2018) 56 NSA3 | DOI: 10.1530/endoabs.56.NSA3

ECE2018 New Scientific Approaches (1) (6 abstracts)

Reprgrammin strategies to obtain functional endocrine units; focus on the adrenal cortex

Leonardo Guasti


Primary or secondary adrenal insufficiency (AI) results from adrenal failure or impairment of the hypothalamic-pituitary axis, respectively. In both cases, the cortex fails to secrete sufficient amounts of glucocorticoids and adrenal androgens, but in primary AI the clinical consequences of aldosterone deficiency make this a more lethal condition. The most frequent cause of primary AI is autosomal recessive congenital adrenal hyperplasia (CAH), which results from defects in enzymes involved in steroid biosynthesis. Patients with AI need life-long management with exogenous steroids: this can be challenging as no drug suitably mimics the diurnal pattern of cortisol, and objective variables measuring the quality of replacement therapy are lacking. Fine-tuning of replacement therapy leaves only a narrow margin for improvement: under-replacement can result in severe impairment of well-being and incipient crisis, while even subtle, chronic over-replacement has the potential to contribute to excess morbidity including obesity, osteoporosis, hypertension and impaired glucose tolerance. Therefore, better treatment solutions are urgently needed. The ability to generate donor-specific and functional adrenocortical-like cells would facilitate i) the next generation of cell-based treatments for AI; ii) the modelling of adrenal specific diseases and iii) the testing of personalised interventions on cells derived from patients. We have generated human induced steroidogenic cells (hiSCs) using a variety of human cell sources, such as fibroblasts, blood- and urine-derived. reprogramming was achieved threough forced expression of Steroidogenic Factor-1 and activation of protein kinase-A pathway in the presence of luteinizing hormone- releasing hormone. hiSCs have ultrastructural features resembling steroid-secreting cells, express steroidogenic enzymes and secrete steroid hormones in response to both pharmacological and physiological stimuli. hiSCs can successfully engraft into the mouse kidney capsule and can undergo differentiation when injected intra-adrenally. Importantly, the hypocortisolism of hiSCs derived from patients with adrenal insufficiency due to congenital adrenal hyperplasia can be rescued by expressing the wild-type version of the defective disease-causing enzymes. This technology 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.

Volume 56

20th European Congress of Endocrinology

Barcelona, Spain
19 May 2018 - 22 May 2018

European Society of Endocrinology 

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