Abstract
SummaryAdrenal 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.
Highlights
The adrenal cortex is a major steroid-producing organ, secreting glucocorticoids under the control of adrenocorticotropic hormone (ACTH), secreted by the anterior pituitary gland, and mineralocorticoids under the control of the renin-angiotensin system
Establishment of Human Primary Cultures from Different Cell Sources Primary cultures of human urine-derived stem cells (USCs), lateoutgrowth endothelial progenitor cells (L-EPCs), and fibroblasts were initially established from healthy donors (Figure S1)
Because L-EPCs are phenotypically indistinguishable from bone-marrow-derived endothelial cells (BMECs) (Yoder et al, 2012), the latter were used in our experiments
Summary
The adrenal cortex is a major steroid-producing organ, secreting glucocorticoids under the control of adrenocorticotropic hormone (ACTH), secreted by the anterior pituitary gland, and mineralocorticoids under the control of the renin-angiotensin system. 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 (Merke and Bornstein, 2005). Better treatment solutions are urgently needed (Bornstein et al, 2016)
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