Characterization of Aldosterone-producing Cell Cluster (APCC) at Single-cell Resolution.
Characterization of Aldosterone-producing Cell Cluster (APCC) at Single-cell Resolution.
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DOI：
10.1210/clinem/dgac394
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发表时间：
2022-08-18
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肾上腺皮质由球状带(ZG)、束状带(ZF)和网状带组成。醛固酮生成细胞团(APCCs)强表达醛固酮合成酶(CYP11B2)，常见于成人肾上腺，其体细胞突变在醛固酮腺瘤(APAs)中也可检测到。原发性醛固酮增多症主要由APAS或特发性醛固酮增多症(IHA)引起。我们推测，APCCs正在引起IHA，是APA的前驱物质。然而，APCCs的基因表达特征，尤其是APCCs的发育还不是很清楚。本研究旨在分析APCCs在单细胞分辨率下的转录组，并推测其发育轨迹。对2例成人肾上腺进行了单细胞RNA测序。免疫组织化学分析证实两个肾上腺均有APCCs。获得了2928个肾上腺细胞的scRNA-seq数据，基于非监督聚类和标记基因表达鉴定了1765个肾上腺皮质细胞。肾上腺皮质细胞分为6个簇，其中3个簇(923个细胞)由APCC/ZG细胞组成。通过进一步的亚聚类，将APCC/ZG细胞划分为3个簇(簇C1、C2和C3)，最终确定为APCC簇(C3)和ZG簇(C1)。C2簇似乎是ZG到ZF的过渡细胞。RNA速度分析推测了ZG-CLUSTER-C1到APCC-CLUSTER-C3的发展方向。ScRNA-seq还显示，许多细胞色素P11B2阳性细胞的细胞色素P11B1和/或细胞色素P17A1阳性，这是皮质醇，但不是醛固酮的生产。我们的结果揭示了APCC在单细胞分辨率下的基因表达特征，并表明一些ZG细胞重塑为APCC。
The adrenal cortex consists of zona glomerulosa (ZG), fasciculata (ZF), and reticularis. Aldosterone-producing cell clusters (APCCs) that strongly express aldosterone synthase (CYP11B2) are frequently found in adult adrenals and harbor somatic mutations that are also detected in aldosterone-producing adenomas (APAs). Primary aldosteronism is mainly caused by APAs or idiopathic hyperaldosteronism (IHA). We presume that APCCs are causing IHA and are precursors of APAs. However, the gene expression characteristics and especially the development of APCCs are not well understood. This study aimed to analyze the transcriptome of APCCs at single-cell resolution and infer the developmental trajectory. Single-cell RNA sequencing (scRNA-seq) of 2 adult adrenals was performed. Immunohistochemical analyses confirmed the 2 adrenals had APCCs. scRNA-seq data of 2928 adrenal cells were obtained and 1765 adrenocortical cells were identified based on unsupervised clustering and the marker gene expression. The adrenocortical cells were divided into 6 clusters, of which 3 clusters (923 cells) were composed of APCC/ZG cells. By further subclustering, the APCC/ZG cells were divided into 3 clusters (clusters C1, C2, and C3), we finally identified APCC cluster (C3) and ZG cluster (C1). Cluster C2 seemed to be ZG-to-ZF transitional cells. RNA velocity analysis inferred the developmental direction from cluster ZG-cluster-C1 to APCC-cluster-C3. The scRNA-seq additionally revealed that many CYP11B2-positive cells were positive for CYP11B1 and/or CYP17A1, which were essential for cortisol but not for aldosterone production. Our results revealed the gene expression characteristics of APCC at single-cell resolution and show that some ZG cells remodel to APCC.
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