Department of Pediatrics, Radboud Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
Eur J Endocrinol. 2022 Sep 29;187(5):607-615. doi: 10.1530/EJE-22-0143. Print 2022 Nov 1.
Testicular adrenal rest tumors (TART) are a common complication of unknown cellular origin in patients with congenital adrenal hyperplasia (CAH). These benign tumors have both adrenal and testicular characteristics and are hypothesized to either derive from cells of adrenal origin from the fetal adrenogonadal primordium or by atypical differentiation of adult Leydig-progenitor cells.
This study aims to unravel the identity and etiology of TART.
Co-expression of adrenal-specific CYP11B1 and Leydig cell-specific HSD17B3 in TART was studied using immunohistochemistry. We studied the possibility of TART being derived from atypical differentiation of adult Leydig-progenitor cells by the quantification of adrenal-specific enzyme expression upon adrenocorticotrophic hormone (ACTH)-like stimulation of ex vivo cultured platelet-derived growth factor receptor alpha-positive cells. By comparing the transcriptome of TART (n = 16) with the transcriptome of fetal adrenal (n = 13), fetal testis (n = 5), adult adrenal (n = 11), and adult testis (n = 10) tissues, we explored the identity of TART.
We demonstrate co-expression of adrenal-specific CYP11B1 and testis-specific HSD17B3 in TART cells, indicating the existence of a distinct TART cell exhibiting both adrenal and testicular characteristics. Ex vivo cultured adult Leydig-progenitor cells did not express the ACTH-receptor MC2R but did express CYP11B1 upon stimulation. Unsupervised clustering of transcriptome data showed that TART was most similar to adult adrenal tissue, followed by adult testis tissue, and least similar to either fetal tissue.
Our data suggest that TART is induced - most likely via activation of a cAMP/protein kinase A-dependent receptor - from a progenitor cell into a unique mature adrenal-like cell type, sometimes exhibiting both adrenal and testicular features.
睾丸肾上腺残迹瘤（TART）是先天性肾上腺皮质增生症（CAH）患者中一种常见的、来源不明的细胞并发症。这些良性肿瘤同时具有肾上腺和睾丸的特征，推测来源于胎儿肾上腺性腺原基的肾上腺源性细胞，或者来源于成体 Leydig 祖细胞的非典型分化。
本研究旨在阐明 TART 的特性和病因。
使用免疫组织化学研究 TART 中肾上腺特异性 CYP11B1 和睾丸特异性 HSD17B3 的共表达。我们通过定量分析促肾上腺皮质激素（ACTH）样刺激体外培养血小板衍生生长因子受体α阳性细胞后肾上腺特异性酶的表达，研究 TART 是否来源于成体 Leydig 祖细胞的非典型分化。通过比较 TART（n=16）、胎儿肾上腺（n=13）、胎儿睾丸（n=5）、成体肾上腺（n=11）和成年睾丸（n=10）的转录组，我们探索了 TART 的特性。
我们在 TART 细胞中证明了肾上腺特异性 CYP11B1 和睾丸特异性 HSD17B3 的共表达，表明存在一种具有独特的肾上腺和睾丸特性的 TART 细胞。体外培养的成体 Leydig 祖细胞不表达 ACTH 受体 MC2R，但在刺激后表达 CYP11B1。转录组数据的无监督聚类表明，TART 与成体肾上腺组织最相似，其次是成体睾丸组织，与胎儿组织最不相似。
我们的数据表明，TART 是通过激活 cAMP/蛋白激酶 A 依赖性受体，由祖细胞诱导分化为一种独特的成熟的肾上腺样细胞类型，有时同时表现出肾上腺和睾丸的特征。
