Modeling human prenatal adrenocortical functional zonation dynamics from pluripotent stem cells

Area of Science:

• Endocrinology
• Developmental Biology
• Stem Cell Biology

Background:

• The adrenal cortex exhibits a complex zonal architecture essential for steroid hormone production.
• This architecture arises from the differentiation of progenitor cells within a specific niche.

Purpose of the Study:

• To establish a human pluripotent stem cell-derived adrenal organoid system that recapitulates adrenal cortex development.
• To investigate the signaling pathways and genetic factors involved in adrenal zonation and differentiation.
• To provide a platform for studying adrenal diseases and developing regenerative strategies.

Main Methods:

• Utilized human pluripotent stem cells to generate adrenal organoids.
• Investigated the roles of RSPO3/WNT signaling and ACTH in adrenal progenitor specification and differentiation.
• Studied the effects of NR0B1 loss on adrenal development, modeling X-linked adrenal hypoplasia congenita.
• Reconstituted adrenal zonation in vivo by encapsulating definitive zone cells with capsule cells.

Main Results:

• The organoid system faithfully recapitulates human adrenal development, including zonal architecture and steroid hormone production (cortisol and androgens).
• RSPO3/WNT signaling from the capsule specifies definitive zone progenitors.
• Loss of NR0B1 leads to impaired definitive zone specification and direct conversion to the fetal zone, mimicking congenital adrenal hypoplasia.
• Encapsulated organoids demonstrated ACTH responsiveness and produced key adrenal hormones in vivo.

Conclusions:

• The developed adrenal organoid platform is a powerful tool for dissecting human adrenal development.
• This model provides insights into the mechanisms underlying adrenal zonation and diseases like X-linked adrenal hypoplasia congenita.
• The organoid system lays the foundation for regenerative medicine approaches to adrenal disorders.