The role of testicular peritubular cells in human testicular ageing

睾丸管周细胞在人类睾丸衰老中的作用

• 批准号: 265636604
• 负责人: Dr. Georg Josef Arnold
• 金额: --
• 依托单位: Deutsches Primatenzentrum GmbH - Leibniz-Institut für Primatenforschung (DPZ)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/265636604?language=en
• 关键词: role; testicular; peritubular; cells; human

Age-associated morphological and functional changes of the human testis include reduced endocrine functions and impaired spermatogenesis. The underlying mechanisms are not well known, but the cells building the walls of seminiferous tubules may play a role. Hints of an involvement come from the fibrotic changes that occur in the tubular wall during ageing and stereological studies, which indicate that these testicular peritubular cells (TPCs) decrease in numbers. Importantly, in contrast to other human testicular cells, human TPCs (HTPCs) are accessible for cellular studies and the evolving insights identify them as a central player in the human testis. In particular, via secreted factors they participate in paracrine interactions in the testis and may contribute to the process of spermatogenesis /the spermatogonial stem cell niche. They are responsible for intratesticular transport of sperm and may provide precursors for the Leydig cell population. Our preliminary studies in HTPCs show that when propagated in culture, they age. Cellular replicative senescence, i.e. reduced ability to divide, is accompanied by increases in cell size, expression of beta-galactosidase (ß-Gal) and reduced levels of androgen receptors, indicative of other unknown changes in HTPC-functions and products. We hypothesize that this also occurs in vivo in man and in long-lived non-human primates. Consequences of HTPC-ageing collectively may contribute to the age-associated decline of testicular functions in man. The study of HTPCs and the use of translational non-human primate animal models are suggested to explore mechanisms of testicular ageing. Thus, to test our hypothesis we plan (1) a series of studies using pre-senescent and senescent HTPCs. Cellular and molecular characterization of senescent cells include a comprehensive secretome profile to define the senescence-associated secretory phenotype (SASP) and to analyze consequences of in vitro ageing. Actions of altered secretory factors will be explored in cell culture studies. Functional assays include contractility assays and examination of smooth muscle markers as well as stem cell characteristics. (2) Complementary in vitro and in situ studies in testicular samples from young adult and old, yet healthy non-human primates (Common marmoset monkey (Callithrix jacchus) and Rhesus monkey (Macaca mulatta)) will be performed. These translational animal models largely rule out confounding health-issues and allow us to discriminate between age- and illness-associated changes of the testis, which is not entirely possible in humans. Studies involving whole transcriptome analyses, and testicular morphology, will be complemented by the study of isolated PTCs from young adult and old Callithrix jacchus. We anticipate that the results of our project will elucidate mechanisms of testicular ageing. The insights gained may lead to novel approaches to intercept testicular consequences of ageing.

睾丸炎相关的人类睾丸形态和功能变化包括内分泌功能降低和精子发生受损。其潜在机制尚不清楚，但构建曲细精管壁的细胞可能发挥了作用。参与的暗示来自于在衰老和体视学研究期间在管壁中发生的纤维化变化，其表明这些睾丸管周细胞（TPC）数量减少。重要的是，与其他人类睾丸细胞相比，人类TPC（HTPC）可用于细胞研究，并且不断发展的见解将其确定为人类睾丸中的核心参与者。特别是，通过分泌因子，它们参与睾丸中的旁分泌相互作用，并可能有助于精子发生/精原干细胞生态位的过程。它们负责精子的睾丸内运输，并可能为Leydig细胞群提供前体。我们对HTPC的初步研究表明，当在培养中繁殖时，它们会老化。细胞复制性衰老，即分裂能力降低，伴随着细胞大小的增加、β-半乳糖苷酶（β-Gal）的表达和雄激素受体水平的降低，指示HTPC功能和产物的其他未知变化。我们假设，这也发生在体内的人和长寿的非人类灵长类动物。HTPC老化的后果可能共同导致与年龄相关的睾丸功能下降在man. The研究HTPC和使用翻译的非人灵长类动物模型的建议，以探讨睾丸老化的机制。因此，为了验证我们的假设，我们计划（1）使用衰老前和衰老HTPC进行一系列研究。衰老细胞的细胞和分子表征包括全面的分泌组概况，以定义衰老相关的分泌表型（SASP）和分析体外衰老的后果。将在细胞培养研究中探索改变的分泌因子的作用。功能测定包括收缩性测定和平滑肌标志物以及干细胞特征的检查。 (2)将对年轻成年和老年但健康的非人灵长类动物（普通绒猴（Callithrix jacchus）和恒河猴（Macaca mulatta））的睾丸样本进行补充性体外和原位研究。这些转化动物模型在很大程度上排除了混淆的健康问题，并使我们能够区分睾丸的年龄和疾病相关变化，这在人类中是不完全可能的。涉及全转录组分析和睾丸形态学的研究将通过对年轻成年和老年Callithrix jacchus的分离PTC的研究来补充。我们预计，我们的项目的结果将阐明睾丸老化的机制。所获得的见解可能会导致新的方法来拦截老化的睾丸后果。

项目成果

Insights into replicative senescence of human testicular peritubular cells

深入了解人类睾丸管周细胞的复制衰老

• DOI: 10.1038/s41598-019-51380-w
• 发表时间: 2019
• 期刊: Scientific Reports
• 影响因子: 4.6
• 作者: Schmid N;Flenkenthaler F;Stöckl JB;Dietrich KG;Köhn FM;Schwarzer JU;Kunz L;Luckner M;Wanner G;Arnold GJ;Fröhlich T;Mayerhofer A.
• 通讯作者: Mayerhofer A.