GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE291nnn/GSE291218/suppl/filelist.txtftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE291nnn/GSE291218/suppl/GSE291218_RAW.tarftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE291nnn/GSE291218/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE291218GEOGSEfalseFunctional reconstitution of adrenocortical transdifferentiation from human pluripotent stem cellsProper 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.2026/05/05GSE291218GSM8831089GSM8831100GSM8831101GSM8831098GSM8831099GSM8831104GSM8831105GSM8831102GSM8831103GSM8831092GSM8831093GSM8831090GSM8831091GSM8831096GSM8831097GSM8831094GSM883109530173291218Homo sapiens[41795428]