在人多能干细胞衍生的皮质-髓质样组装体中模拟人类胚胎期肾上腺发育
Modeling human embryonic adrenogenesis in pluripotentstem cell-derived corticomedullar-like assembloids
肾上腺由两种来源不同的细胞组成：皮质来自中间中胚层的类固醇生成前体，髓质来自迁移的神经嵴细胞，二者在胚胎中协同发育，此前难以在体外重现。研究者用人类多能干细胞（可分化成身体各种细胞的干细胞）构建了“组装体”——把两类细胞团组合在一起的三维结构，意外发现其中出现了能生成嗜铬细胞（分泌肾上腺素等激素的细胞）的Schwann细胞前体。通过分析细胞间的信号传递，他们找到了FGF9驱动嗜铬前体扩增的机制，最终得到的皮质-髓质样组装体能分泌类固醇和儿茶酚胺（两类肾上腺激素），并对促肾上腺皮质激素有反应。这为研究肾上腺发育和疾病、以及未来细胞治疗提供了平台。尚未经同行评审。
为什么推荐给您：首次用干细胞组装体同时重现肾上腺皮质与髓质发育及激素分泌，属重要新平台技术。
不需要生物学背景，多打比方
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摘要Abstract
During embryogenesis, the cortical and medullary compartments of the adrenal gland emerge from two distinct sources: intermediate mesoderm-derived steroidogenic progenitors that comprise the cortex, and migratory neural crest-derived catecholaminergic progenitors that give rise to the medulla. The distinct cellular origins and paracrine signaling environments that foster induction, differentiation, and/or migration of cortical and medullary layers present challenges to recapitulating their co-emergence and incorporation in a human pluripotent stem cell (hPSC) based system. To address this, we developed an approach for modeling the adreno-gonadal primordium (AGP) in compound organoids that are organized along a gradient of NR5A1 expression and which unexpectedly incorporate SOX10-expressing Schwann cell precursors that ultimately generate chromaffin cells. Deconstruction of paracrine signaling within AGP-like organoids (AGPLOs) identified a fibroblast growth factor 9 (FGF9)-driven mechanism that expands bridge cell-like chromaffin progenitors and correlates to paracrine signaling cues encountered by physiological correlates along their migration corridor to the cortex in vivo. Combination of NR5A1-expressing cells with chromaffin cell clusters generated corticomedullar-like assembloids (CMLAs) that generated steroids and catecholamines and were responsive to adrenocorticotropic hormone. This work establishes a platform for modeling the reciprocal signaling relationships that drive adrenal gland development and function in health and disease and provides an approach for generating hPSC-derived adrenal cells/tissues that can be applied therapeutically.