Abstract：
The mechanisms leading to adrenal cortex development and steroid synthesis in humans remain poorly understood due to the paucity of model systems. Herein, we recapitulate human fetal adrenal cortex specification processes through stepwise induction of human-induced pluripotent stem cells through posterior intermediate mesoderm-like and adrenocortical progenitor-like states to ultimately generate fetal zone adrenal-cortex-like cells (FZLCs), as evidenced by histomorphological, ultrastructural, and transcriptome features and adrenocorticotropic hormone (ACTH)-independent Δ5 steroid biosynthesis. Furthermore, FZLC generation is promoted by SHH and inhibited by NOTCH, ACTIVIN, and WNT signaling, and steroid synthesis is amplified by ACTH/PKA signaling and blocked by inhibitors of Δ5 steroid synthesis enzymes. Finally, NR5A1 promotes FZLC survival and steroidogenesis. Together, these findings provide a framework for understanding and reconstituting human adrenocortical development in vitro, paving the way for cell-based therapies of adrenal insufficiency.
摘要：
由于模型系统的缺乏，导致人类肾上腺皮质发育和类固醇合成的机制仍然知之甚少。在这里，我们通过逐步诱导人类诱导的多能干细胞，通过后中间中胚层样和肾上腺皮质祖细胞样状态，最终生成胎儿区肾上腺皮质样细胞（FZLCs），概述了人类胎儿肾上腺皮质规范过程。正如组织形态学所证明的，超微结构，转录组特征和促肾上腺皮质激素（ACTH）非依赖性Δ5类固醇生物合成。此外，SHH促进FZLC生成，NOTCH抑制FZLC生成，ACTIVIN,和WNT信令，和类固醇合成通过ACTH/PKA信号传导扩增，并被Δ5类固醇合成酶的抑制剂阻断。最后,NR5A1促进FZLC存活和类固醇生成。一起,这些发现为理解和重建体外人类肾上腺皮质发育提供了一个框架，为肾上腺功能不全的细胞疗法铺平了道路。
