Nicole Bechmann

Aim: Regenerative and curative strategies would be desirable for neurodegenerative and adrenal diseases, and multipotent adrenal stem cells are considered as promising biological tools for this purpose. Stem-like cells with the potential to proliferate and differentiate in vivo and in vitro were discovered in both cortex and medulla of the adrenal gland. Previously, it was demonstrated that nestin-positive progenitors in the cortex and medulla, play an important role under stress. In the present study, the cultivation of these cells was optimized and their growth in vitro was characterized. Methods: Primary cells from the adrenal cortex and medulla from Nes-GFP mice were isolated and the in vitro culture conditions promoting the growth of stem and progenitor cells using different 3-dimensional (3D) spheroid culture models were optimized. Results: Both cortical and medullary cells could be cultured for at least one month under several different low-adherence conditions maintaining their viability and potential to differentiate. Medullary cells grew faster than cortical cells. Endothelin did not affect the cultures. Conclusions: Adrenomedullary and adrenocortical nestin-positive progenitor cells can be cultured long-term in 3D cultures maintaining their proliferation and differentiation capabilities. Such multidimensional models can potentially be used for drug screening to develop personalized medicines or for transplantation to treat neurodegenerative disorders or adrenal diseases, such as adrenal insufficiency.

Corticosteroids regulate vital processes, including stress responses, systemic metabolism, and blood pressure. Here, we show that corticosteroid synthesis is related to the polyunsaturated fatty acid (PUFA) content of mitochondrial phospholipids in adrenocortical cells. Inhibition of the rate-limiting enzyme of PUFA synthesis, fatty acid desaturase 2 (FADS2), leads to perturbations in the mitochondrial lipidome and diminishes steroidogenesis. Consistently, the adrenocortical mitochondria of Fads2 −/− mice fed a diet with low PUFA concentration are structurally impaired and corticoid levels are decreased. On the contrary, FADS2 expression is elevated in the adrenal cortex of obese mice, and plasma corticosterone is increased, which can be counteracted by dietary supplementation with the FADS2 inhibitor SC-26192 or icosapent ethyl, an eicosapentaenoic acid ethyl ester. In humans, FADS2 expression is elevated in aldosterone-producing adenomas compared to non-active adenomas or nontumorous adrenocortical tissue and correlates with expression of steroidogenic genes. Our data demonstrate that FADS2-mediated PUFA synthesis determines adrenocortical steroidogenesis in health and disease.