{"doi":"10.1101/2025.05.24.655925","title":"Reconstitution of adrenocortical functional zonation from human pluripotent stem cells","abstract":"Summary The adrenal cortex produces essential steroid hormones through a concentric zonal architecture, established by the centripetal trans-differentiation of subcapsular progenitors within a capsule-derived niche. To capture this complexity, we establish a human pluripotent stem cell-derived adrenal organoid system that faithfully recapitulates this process. RSPO3/WNT signaling from the capsule specifies definitive zone (DZ) progenitors from the adrenal primordium, which then differentiate into a cortisol-producing transitional zone and an androgen-producing fetal zone under the influence of RSPO3 and ACTH. Loss of NR0B1 impairs DZ specification and triggers direct adrenal primordium-to-fetal zone conversion, mirroring the mechanism of X-linked adrenal hypoplasia congenita. When DZ cells are encapsulated with capsule cells separately derived from pluripotent stem cells, they reconstitute zonation in vivo, forming ACTH-responsive tissue that produces both cortisol and androgens. This organoid platform offers a powerful tool to dissect human adrenal development and establishes a foundation for regenerative therapies targeting adrenal diseases.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":566886,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9422,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1062463,"name":"Eoin C. Whelan","orcid":"0000-0003-0842-7722","position":1,"is_corresponding":false},{"id":1470814,"name":"Takeshi Sato","orcid":"0000-0002-5836-7273","position":2,"is_corresponding":false},{"id":723165,"name":"David G. Stouffer","orcid":"0009-0008-9453-8819","position":3,"is_corresponding":false},{"id":1471136,"name":"Adrian N. Leu","orcid":null,"position":4,"is_corresponding":false},{"id":714265,"name":"Jerome F. Strauss","orcid":"0000-0002-6876-1880","position":5,"is_corresponding":false},{"id":369854,"name":"Richard J. Auchus","orcid":"0000-0001-6815-6181","position":6,"is_corresponding":false},{"id":258987,"name":"Kotaro Sasaki","orcid":"0000-0002-5604-2651","position":7,"is_corresponding":false},{"id":890360,"name":"Michinori Mayama","orcid":"0000-0001-6630-9869","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:56:40.491968Z","pmid":"40501586","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}