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Functional reconstitution of adrenocortical transdifferentiation from human pluripotent stem cells

ABSTRACT: Proper prenatal adrenal cortex development is essential to prevent life-threatening adrenal insufficiency. This process relies on self-renewing progenitor cells within a capsule (Cap)-derived niche of the definitive zone (DZ) and trans-differentiation into cortisol-producing transitional and androgen-producing fetal zones. However, species-specific limitations in rodent models hinder mechanistic insights. To address this, we developed a human iPSC-derived organoid system that mimics prenatal adrenal development. Our advanced platform efficiently generates DZ-like cells (DZLCs) and Cap-like cells (CapLCs), revealing that DZLCs arise from adrenal primordium-like cells (APLCs) and are sustained via CapLC-derived RSPO3/WNT signaling. These DZLCs trans-differentiate into transitional and fetal zone-like cells (FZLCs) through ACTH and RSPO3 signaling. Notably, NR0B1 loss impairs DZLC specification while driving direct APLC-to-FZLC conversion, recapitulating NR0B1 mutation-associated X-linked adrenal hypoplasia congenita. Notably, DZLCs encapsulated with CapLCs form ACTH-responsive, cortisol-producing cortical tissue in vivo, demonstrating therapeutic potential. These organoid models offer a powerful platform for adrenal research and lay the groundwork for cell-based therapies for adrenal insufficiency.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291218 | GEO | 2026/05/05

REPOSITORIES: GEO

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Project description:This a model from the article: A mechanistic model of ACTH-stimulated cortisol secretion. Dempsher DP, Gann DS, Phair RD. Am J Physiol 1984 Apr;246(4 Pt 2):R587-96 6326602 , Abstract: Adrenal secretory rates of cortisol and arterial concentrations of adrenocorticotropin (ACTH) were measured in conscious trained dogs subjected to intravenous infusion of ACTH. To investigate the causal relation of ACTH to the secretion of cortisol, a mechanistic mathematical model based on current hypotheses of adrenocortical function was constructed and tested. It is widely believed that ACTH stimulates cortisol secretion through adenosine 3',5'-cyclic monophosphate (cAMP), which provides substrate cholesterol by activating cholesterol ester hydrolase and facilitating transport of cholesterol to the side-chain cleavage enzyme. In addition, cholesterol modulates its own synthesis by inhibiting beta-hydroxy-beta-methylglutaryl (HMG)-CoA reductase in the adrenocortical cell. These and other steps in the biosynthetic reaction sequence were described using differential equations subject to the additional constraints imposed by available measurements of intracellular quantities. The resulting model is consistent with many of the known characteristics of the canine adrenal response to ACTH. In this model, steady-state nonlinearities arise from cooperative binding of cAMP to its receptor protein and saturation of mitochondrial pregnenolone transport. The transient response is dominated by a depletable pool of intracellular free cholesterol. Other inferences based on the model are presented, and a quantifiable cellular basis for increased adrenal sensitivity to ACTH is proposed. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Dempsher DP, Gann DS, Phair RD. (1984) - version03 The original CellML model was created by: Lloyd, Catherine, May c.lloyd@aukland.ac.nz The University of Auckland The Bioengineering Institute This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:Background Deficient glucocorticoid biosynthesis leading to adrenal insufficiency is life-threatening and is associated with significant co-morbidities. The affected pathways underlying the pathophysiology of co-morbidities due to glucocorticoid deficiency remain poorly understood and require further investigation. Methods To explore the pathophysiological processes related to glucocorticoid deficiency, we have performed global transcriptional, post-transcriptional and metabolic profiling of a cortisol-deficient zebrafish mutant with a disrupted ferredoxin (fdx1b) system. Findings fdx1b−/− mutants show pervasive reprogramming of metabolism, in particular of glutamine-dependent pathways such as glutathione metabolism, and exhibit changes of oxidative stress markers. The glucocorticoid-dependent post-transcriptional regulation of key enzymes involved in de novo purine synthesis was also affected in this mutant. Moreover, fdx1b−/− mutants exhibit crucial features of primary adrenal insufficiency, and mirror metabolic changes detected in primary adrenal insufficiency patients. Interpretation Our study provides a detailed map of metabolic changes induced by glucocorticoid deficiency as a consequence of a disrupted ferredoxin system in an animal model of adrenal insufficiency. This improved pathophysiological understanding of global glucocorticoid deficiency informs on more targeted translational studies in humans suffering from conditions associated with glucocorticoid deficiency.fdx1b-/- mutants show a pervasive reprogramming of metabolism, in particular of glutamine-dependent pathways such as glutathione metabolism, and exhibit changes of oxidative stress markers. The glucocorticoid-dependent post-transcriptional regulation of key enzymes involved in de novo purine synthesis was also affected in this mutant. Moreover, fdx1b-/- mutants exhibit crucial features of primary adrenal insufficiency, and mirror metabolic changes detected in primary adrenal insufficiency patients. Our study provides a detailed map of metabolic changes induced by glucocorticoid-deficiency as a consequence of a disrupted ferredoxin system in an animal model of adrenal insufficiency. This improved pathophysiological understanding of global glucocorticoid deficiency informs on more targeted translational studies in humans suffering from conditions associated with glucocorticoid deficiency.

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Functional reconstitution of adrenocortical transdifferentiation from human pluripotent stem cells

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