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首页> 外文期刊>Human Reproduction >Expression patterns of DLK1 and INSL3 identify stages of Leydig cell differentiation during normal development and in testicular pathologies, including testicular cancer and Klinefelter syndrome
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Expression patterns of DLK1 and INSL3 identify stages of Leydig cell differentiation during normal development and in testicular pathologies, including testicular cancer and Klinefelter syndrome

机译：DLK1和INSL3的表达模式可识别正常发育过程中以及睾丸病变（包括睾丸癌和Klinefelter综合征）中的Leydig细胞分化阶段

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study question: What is the differentiation stage of human testicular interstitial cells, in particular Leydig cells (LC), within micronodules found in patients with infertility, testicular cancer and Klinefelter syndrome? summaryanswer: The Leydig-and peritubular-cell populations in testes with dysgenesis contain an increased proportion of undifferentiated cells when compared with control samples, as demonstrated by increased delta-like homolog 1 (DLK1) and decreased insulin-like peptide 3 (INSL3) expression. what is known already: Normal LC function is essential for male development and reproduction. Signs of LC failure, including LC micronodules, are often observed in patients with reproductive disorders. study design, size, participants: In this retrospective study, a panel of markers and factors linked to the differentiation of LCs was investigated in 33 fetal and prepubertal human specimens and in 58 adult testis samples from patients with testicular germ cell tumours, including precursor carcinoma in situ (CIS), infertility or Klinefelter syndrome. participants/materials, setting, methods: The expression patterns of DLK1, INSL3, chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII), cytochrome P450, family 11, subfamily A, polypeptide 1 (CYP11A1) and smooth muscle actin (SMA) were investigated by immunohistochemistry and quantitative RT-PCR. The percentage of positive LCs was estimated and correlated to total LC numbers and serum levels of reproductive hormones. main results and the role of chance: DLK1, INSL3 and COUP-TFII expression changed during normal development and was linked to different stages of LC differentiation: DLK1 was expressed in all fetal LCs, but only in spindle-shaped progenitor cells and in a small subset of polygonal LCs in the normal adult testis; INSL3 was expressed in a subset of fetal LCs, but in the majority of adult LCs; and COUP-TFII was expressed in peritubular and mesenchymal stroma cells at all ages, in fetal LCs early in gestation and in a subset of adult LCs. CYP11A1 was expressed in the majority of LCs regardless of age and pathology andwas the best general LC marker examined here. SMAwas weakly expressed in peritubular cells in the fetal and infantile testis, but strongly expressed in the adult testis. In pathological testes, the numbers of DLK1-positive interstitial cells were increased. The proportion of DLK1-positive LCs correlated with total LC numbers (R = 0.53; P 0.001) and was higher in testis with enlargement of the peritubular layers (P 0.01), which was also highly associated with DLK1 expression in the peritubular compartment (P 0.001). INSL3 expression was absent in some, but not all LC micronodules, and in the majority of LCs, it was mutually exclusive of DLK1. limitations, reasons for caution: The number of samples was relatively small and no true normal adult controls were available. True stereology was not used for LC counting, instead LCs were counted in three fields of 0.5 糾2 surface for each sample. wider implications of the findings: The population of LCs, especially those clustered in large nodules, are heterogeneous and comprise cells at different stages of differentiation. The study demonstrated that the differentiation and function of LCs, and possibly also peritubular cells, are impaired in adult men with testicular pathologies including testis cancer and Klinefelter syndrome.
机译：研究问题：在不育，睾丸癌和克氏综合征患者中发现的小结节内，人类睾丸间质细胞，特别是莱迪希细胞（LC）的分化阶段是什么？摘要答案：发育不全的睾丸中的Leydig和肾小管周围细胞群与对照组样品相比，未分化细胞的比例增加，这可通过增加的delta样同源物1（DLK1）和降低的胰岛素样肽3（INSL3）表达来证明。 。已经知道的：正常的LC功能对于男性发育和繁殖至关重要。在患有生殖系统疾病的患者中经常观察到LC衰竭的迹象，包括LC微小结节。研究设计，规模，参与者：在这项回顾性研究中，对33例胎儿和青春期前人类标本以及58例睾丸生殖细胞肿瘤患者（包括前体癌）的成人睾丸样品进行了一系列与LC分化相关的标志物和因素的研究原位（CIS），不育或Klinefelter综合征。参与者/材料，环境，方法：DLK1，INSL3，鸡卵清蛋白上游启动子转录因子2（COUP-TFII），细胞色素P450，家族11，亚家族A，多肽1（CYP11A1）和平滑肌肌动蛋白（SMA）的表达模式通过免疫组织化学和定量RT-PCR研究。估计阳性LC的百分比，并将其与总LC数和血清中的生殖激素水平相关。主要结果和机会的作用：DLK1，INSL3和COUP-TFII表达在正常发育过程中发生变化，并与LC分化的不同阶段有关：DLK1在所有胎儿LC中均有表达，但仅在纺锤状祖细胞和少量胚胎中表达。正常成人睾丸中多边形LC的子集; INSL3在一部分胎儿LC中表达，但在大多数成人LC中表达。 COUP-TFII在各个年龄段的肾小管周围和间质间质细胞中表达，在妊娠早期的胎儿LC和部分成人LC中表达。 CYP11A1在大多数LC中均表达，无论其年龄和病理状况如何，都是此处检测的最佳常规LC标记。 SMA在胎儿和婴儿睾丸的肾小管周细胞中微弱表达，但在成年睾丸中强表达。在病理性睾丸中，DLK1阳性间质细胞数量增加。 DLK1阳性LC的比例与总LC数量相关（R = 0.53; P <0.001），并且在睾丸中随着管周层的增大而增加（P <0.01），这也与DLK1在管周区的表达高度相关（P <0.001）。在某些但不是所有LC微结节中都没有INSL3表达，在大多数LC中，它与DLK1是互斥的。局限性，警告原因：样本数量相对较少，并且没有真正的正常成人对照。真实的立体学没有用于LC计数，而是对每个样品在0.5纠缠表面的三个场中对LC进行计数。研究结果的更广泛含义：LC的种群，特别是聚集在大结节中的LC种群是异质的，并且包含处于不同分化阶段的细胞。该研究表明，成年男性睾丸病变包括睾丸癌和克莱氏综合征的LCs，肾小管周围细胞的分化和功能均受到损害。

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