ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2018) 15 8.14 | DOI: 10.1530/ey.15.8.14

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK


To read the full abstract: Cell Rep. 2018; 22(5): 1236-1249

Primary or secondary adrenal insufficiency (AI) results from adrenal failure or impairment of the hypothalamic-pituitary axis, respectively. The most frequent cause of primary AI is autosomal recessive congenital adrenal hyperplasia (CAH). Patients with AI need life-long treatment with exogenous steroids, which can be challenging, given that currently available formulations do not mimic physiologic cortisol secretion. The ability to generate donor-specific and functional adrenocortical-like cells would facilitate: (1) the next generation of cell-based treatments for AI; (2) the modeling of adrenal-specific diseases; and (3) the testing of personalized interventions on cells derived from patients. Donor- and disease-specific steroidogenic cells as surrogates for disease modeling have been lacking up to now. More significantly, their use could be exploited for the development of cell- based treatment modalities for AI.

Here, the authors show that the use of a single cell fate regulator (SF1/NR5A1), in conjunction with PKA and LHRH signaling, can stably reprogram human adult skin-, blood-, and urine-derived cells into hiSCs. Forced expression of other key TFs involved in adrenogonadal differentiation, alone or in combination, was insufficient to induce hiSCs, nor did their expression with SF1 enhance reprogramming. However, given that there is endogenous expression of DAX1, PBX1, CITED2, and WT1 in non-reprogrammed cells, it is entirely possible that those factors participate in hiSC induction along with SF1, although the higher dosages delivered by their constructs did not improve reprogramming. Activation of the WNT pathway through WNT4 is associated with zona glomerulosa differentiation, which is prevented by PKA activation. Treatment of hiSCs with recombinant WNT4 did not result in changes of zonal- specific markers nor cortisol secretion; it is possible that, in this experimental setting, forced-expression of SF1 bypasses key differentiation events occurring physiologically at the capsule/subcapsular region during the normal self-renewal/zonal specification of the gland. The functionality of hiSCs makes them an unmatched tool to obtain surrogate adrenocortical cells for in vitro disease modeling. With this in mind, the authors derived hiSCs from patients with CAH, showing an altered steroid profile. Importantly, the decrease in cortisol production in hiSCs derived from CAH patients was rescued on expression of the exogenous native forms, irrespective of the defective steroidogenic enzyme. These findings provide an effective tool with many potential applications for studying adrenal pathobiology in a personalized manner and open venues for the development of precision therapies.

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