Impaired testicular signaling of vitamin A and vitamin K contributes to the aberrant composition of the extracellular matrix in idiopathic germ cell aplasia
Impaired testicular signaling of vitamin A and vitamin K contributes to the aberrant composition of the extracellular matrix in idiopathic germ cell aplasia
复制标题
DOI：
10.1016/j.fertnstert.2018.12.002
复制
发表时间：
2019-04-01
影响因子：
6.7
通讯作者：
Salonia, Andrea
中科院分区：
文献类型：
--
作者：
Alfano, Massimo;Pederzoli, Filippo;Salonia, Andrea
目的：研究与特发性生殖细胞发育不全相关的体细胞睾丸微环境的致病特征。设计：横断面研究。设置：生殖医学三级转诊中心。患者：来自特发性非梗阻性无精子症（iNOA）男性的睾丸标本，前瞻性地进行显微解剖睾丸精子提取。在用于组织学的20个标本中，10个也可用于蛋白质组学分析。也使用了具有正常核型和表型的原代Sertoli细胞。干预：iNOA患者根据显微解剖睾丸精子提取时的阳性与阴性精子回收进行二分，并在分离的细胞外基质（ECM）上进行蛋白质组学分析。主要结果测量：阳性与阴性精子回收的睾丸标本的ECM的蛋白质组学分析。基因本体富集用于基于11个去调节的ECM蛋白鉴定上游调节物，其通过免疫组织化学和定量聚合酶链反应验证。连续变量表示为中位数和四分位数interquartile range. Results（s）：生殖细胞发育不全的特点是支持细胞中的视黄酸信号增加，并与基底膜标志物巢蛋白-2和硫酸乙酰肝素蛋白聚糖-2的表达减少相关。间质基质体相关因子IX及其调节因子VKORC 1的水平降低，反而与Leydig细胞中维生素K的信号传导减少相结合。还发现另外八种ECM蛋白的表达发生改变，包括层粘连蛋白-4和层粘连蛋白-5。外周水平的两种维生素的参考范围内的两个队列的iNOA man. Conclusions（S）：我们确定了体细胞人类睾丸微环境的发病特征，提供了两个维生素相关的机制的见解相关的特发性生殖细胞发育不全的分子决定因素。版权所有（C）2018作者。爱思唯尔公司出版代表美国生殖医学会
Objective: To study pathogenic features of the somatic testicular microenvironment associated with idiopathic germ cell aplasia.Design: Cross-sectional study.Setting: Tertiary referral center for reproductive medicine.Patient(s): Testicular specimens from men with idiopathic nonobstructive azoospermia (iNOA) prospectively submitted to microdissection testicular sperm extraction. Of 20 specimens used for histology, 10 were also available for proteomic analysis. Primary Sertoli cells with normal karyotype and phenotype were also used.Intervention(s): Patients with iNOA were dichotomized according to a positive versus negative sperm retrieval at microdissection testicular sperm extraction, and on the isolated extracellular matrix (ECM) the proteomic analysis was performed.Main Outcome Measure(s): Proteomic analysis of the ECM from testicular specimens with positive versus negative spermretrieval. Gene ontology enrichment was used to identify upstream regulators based on the 11 deregulated ECM proteins, which were validated by immunohistochemistry and quantitative polymerase chain reaction. Continuous variables were expressed as medians and interquartile range.Result(s): Germ cell aplasia was characterized by an increased signaling of the retinoic acid in Sertoli cells and associated with decreased expression of the basal membrane markers nidogen-2 and heparan sulfate proteoglycan-2. Decreased levels of the interstitial matrisome-associated factor IX and its regulator VKORC1 were, instead, coupled with decreased signaling of vitamin K in Leydig cells. An altered expression of a further eight ECM proteins was also found, including laminin-4 and laminin-5. Peripheral levels of the two vitamins were within the reference range in the two cohorts of iNOA men.Conclusion(s): We identified the pathogenetic signature of the somatic human testicular microenvironment, providing two vitamin-related mechanistic insights related to the molecular determinants of the idiopathic germ cell aplasia. Copyright (C) 2018 The Authors. Published by Elsevier Inc. on behalf of the American Society for Reproductive Medicine.