人类肾上腺是一个复杂的内分泌组织。关于肾上腺更新的研究仅限于动物模型或人类胎儿。增强我们对成人肾上腺稳态的了解对于深入了解肾上腺疾病（例如肾上腺皮质肿瘤）的发病机制至关重要。在这里，我们对成人正常肾上腺进行了全面的细胞基因组学分析，结合单核 RNA 测序和空间转录组数据来重建肾上腺稳态。正如预期的那样，我们鉴定了肾上腺皮质和髓质各个区域的原代细胞，但我们还发现了其他细胞类型。它们构成了肾上腺微环境，包括主要由大量 M2 巨噬细胞组成的免疫细胞和新细胞群，包括血管内皮细胞和皮质神经内分泌细胞的不同亚群。利用空间转录组和伪时间轨迹分析，我们支持肾上腺皮质细胞维持的向心动力学以及 Wnt/β-连环蛋白、音刺猬和成纤维细胞生长因子途径在成人肾上腺皮质稳态中发挥的重要作用的证据。此外，我们还比较了从六个健康肾上腺和十二个肾上腺皮质腺瘤获得的单核转录谱。该分析揭示了腺瘤样本内细胞群的显着异质性。此外，我们还确定了六个不同的腺瘤特异性簇，每个簇根据类固醇谱和肿瘤突变状态具有不同的分布。总的来说，我们的结果为肾上腺稳态和早期肾上腺皮质肿瘤发生和/或自主类固醇分泌潜在的分子机制提供了新的见解。我们的细胞图谱是研究其他肾上腺相关病理学的强大资源。© 2024 作者。约翰·威利出版的《临床与转化医学》

The human adrenal gland is a complex endocrine tissue. Studies on adrenal renewal have been limited to animal models or human foetuses. Enhancing our understanding of adult human adrenal homeostasis is crucial for gaining insights into the pathogenesis of adrenal diseases, such as adrenocortical tumours. Here, we present a comprehensive cellular genomics analysis of the adult human normal adrenal gland, combining single-nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland homeostasis. As expected, we identified primary cells of the various zones of the adrenal cortex and medulla, but we also uncovered additional cell types. They constitute the adrenal microenvironment, including immune cells, mostly composed of a large population of M2 macrophages, and new cell populations, including different subpopulations of vascular-endothelial cells and cortical-neuroendocrine cells. Utilizing spatial transcriptome and pseudotime trajectory analysis, we support evidence of the centripetal dynamics of adrenocortical cell maintenance and the essential role played by Wnt/β-catenin, sonic hedgehog, and fibroblast growth factor pathways in the adult adrenocortical homeostasis. Furthermore, we compared single-nuclei transcriptional profiles obtained from six healthy adrenal glands and twelve adrenocortical adenomas. This analysis unveiled a notable heterogeneity in cell populations within the adenoma samples. In addition, we identified six distinct adenoma-specific clusters, each with varying distributions based on steroid profiles and tumour mutational status. Overall, our results provide novel insights into adrenal homeostasis and molecular mechanisms potentially underlying early adrenocortical tumorigenesis and/or autonomous steroid secretion. Our cell atlas represents a powerful resource to investigate other adrenal-related pathologies.© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.