Modeling human prenatal adrenocortical functional zonation dynamics from pluripotent stem cells.

Summary

A human PSC-derived adrenal organoid recapitulates prenatal zonation: capsule RSPO3/WNT specifies definitive zone progenitors, which differentiate into cortisol- and androgen-producing zones under RSPO3 and ACTH. NR0B1 loss drives primordium-to-fetal zone conversion, modeling X-linked adrenal hypoplasia congenita; DZ with capsule cells reconstituted ACTH-responsive zonation in vivo.

Key Findings

• PSC-derived adrenal organoids recapitulated capsule-to-core zonation with RSPO3/WNT specifying definitive zone progenitors.
• Under RSPO3 and ACTH, progenitors differentiated into cortisol-producing transitional and androgen-producing fetal zones.
• NR0B1 loss impaired definitive zone specification and triggered primordium-to-fetal zone conversion, mirroring X-linked adrenal hypoplasia congenita.
• Co-encapsulation and implantation of DZ and capsule cells reconstituted ACTH-responsive zonation in vivo.

Clinical Implications

Establishes a foundation for regenerative strategies for adrenal insufficiency and a human model to screen modulators of WNT/ACTH pathways and test gene/cell therapies.

Limitations

• Primarily preclinical organoid and transplantation models; long-term function and safety not established
• Generalizability to adult adrenal physiology and disease heterogeneity remains to be defined

Future Directions

Leverage the platform for drug screening, gene editing for congenital adrenal disorders, and development of transplantation protocols for adrenal insufficiency.