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

IF 20.4 1区医学 Q1 CELL & TISSUE ENGINEERING

Cell stem cell Pub Date : 2026-03-05 DOI:10.1016/j.stem.2026.02.002

Michinori Mayama,Eoin C Whelan,Takeshi Sato,David G Stouffer,Adrian N Leu,Jerome F Strauss,Richard J Auchus,Kotaro Sasaki

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引用次数: 0

Abstract

The adrenal cortex produces essential steroid hormones through a concentric zonal architecture, established by the centripetal transdifferentiation 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.

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用多能干细胞模拟人产前肾上腺皮质功能分区动力学。

肾上腺皮质通过同心圆的区域结构产生必需的类固醇激素，该结构是由包膜下祖细胞在包膜衍生的生态位内向心转分化而建立的。为了捕捉这种复杂性，我们建立了一个人类多能干细胞衍生的肾上腺类器官系统，忠实地概括了这一过程。来自胶囊的RSPO3/WNT信号指定来自肾上腺原基的终区（DZ）祖细胞，然后在RSPO3和ACTH的影响下分化为产生皮质醇的过渡区和产生雄激素的胎儿区。NR0B1的缺失会损害DZ的规范，并触发肾上腺原区到胎儿区的直接转换，反映了x连锁先天性肾上腺发育不全的机制。当DZ细胞被多能干细胞分离出来的囊细胞包裹时，它们在体内重新形成分区，形成acth应答组织，同时产生皮质醇和雄激素。这个类器官平台提供了一个强大的工具来解剖人类肾上腺的发育，并为针对肾上腺疾病的再生治疗奠定了基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell stem cell 生物-细胞生物学

CiteScore

37.10

自引率

2.50%

发文量

151

审稿时长

42 days

期刊介绍： Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.