Genetics and Genomic Medicine Research and Teaching Department, University College London (UCL) Great Ormond Street Institute of Child Health, UCL, London, United Kingdom.
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom.
JCI Insight. 2023 Jul 24;8(14):e168177. doi: 10.1172/jci.insight.168177.
The adrenal glands synthesize and release essential steroid hormones such as cortisol and aldosterone, but many aspects of human adrenal gland development are not well understood. Here, we combined single-cell and bulk RNA sequencing, spatial transcriptomics, IHC, and micro-focus computed tomography to investigate key aspects of adrenal development in the first 20 weeks of gestation. We demonstrate rapid adrenal growth and vascularization, with more cell division in the outer definitive zone (DZ). Steroidogenic pathways favored androgen synthesis in the central fetal zone, but DZ capacity to synthesize cortisol and aldosterone developed with time. Core transcriptional regulators were identified, with localized expression of HOPX (also known as Hop homeobox/homeobox-only protein) in the DZ. Potential ligand-receptor interactions between mesenchyme and adrenal cortex were seen (e.g., RSPO3/LGR4). Growth-promoting imprinted genes were enriched in the developing cortex (e.g., IGF2, PEG3). These findings reveal aspects of human adrenal development and have clinical implications for understanding primary adrenal insufficiency and related postnatal adrenal disorders, such as adrenal tumor development, steroid disorders, and neonatal stress.
肾上腺合成并释放皮质醇和醛固酮等必需的甾体激素，但人类肾上腺发育的许多方面仍不清楚。在这里，我们结合单细胞和批量 RNA 测序、空间转录组学、免疫组织化学和微焦点计算机断层扫描，研究了妊娠前 20 周人类肾上腺发育的关键方面。我们证明了肾上腺的快速生长和血管生成，在外层终末带（DZ）中细胞分裂更多。在中央胎儿带中，类固醇生成途径有利于雄激素的合成，但 DZ 合成皮质醇和醛固酮的能力随时间发展。确定了核心转录调节因子，在 DZ 中局部表达 HOPX（也称为 Hop 同源盒/同源盒仅蛋白）。观察到间充质和肾上腺皮质之间潜在的配体-受体相互作用（例如，RSPO3/LGR4）。生长促进的印迹基因在发育中的皮质中富集（例如，IGF2、PEG3）。这些发现揭示了人类肾上腺发育的方面，并对理解原发性肾上腺功能不全和相关的产后肾上腺疾病具有临床意义，如肾上腺肿瘤的发展、类固醇紊乱和新生儿应激。
