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.

人类睾丸的年龄相关形态和功能变化包括降低内分泌功能和精子发生受损。潜在的机制并不是众所周知，但是建造半频管的壁可能起作用的细胞可能起作用。参与的暗示来自衰老和立体研究期间块茎壁中发生的纤维化变化，这表明这些有证据的周围细胞（TPC）的数量减少。重要的是，与其他人类检测细胞相比，人类TPC（HTPC）可用于细胞研究，而不断发展的见解将其识别为人类睾丸中的核心参与者。特别是，通过分泌的因素，它们参与了睾丸中的旁细胞烯相互作用，可能有助于精子发生 /精子干细胞细胞生态裂。它们负责精子的肠内运输，并可能为Leydig细胞种群提供前体。我们在HTPC中的初步研究表明，在培养中传播时，它们会年龄。细胞复制感受，即降低的分裂能力是通过增加细胞大小，β-半乳糖苷酶（ß-GAL）（ß-GAL）和雄激素受体水平降低来实现的，这表明HTPC函数和产物的其他未知变化。我们假设这也发生在人体和长期寿命的非人类隐私中。 HTPC年龄段的后果统称可能有助于男子的测试功能与年龄相关的下降。建议对HTPC的研究和使用翻译的非人类灵长类动物模型的使用来探索测试衰老的机制。这是为了检验我们的假设，我们计划（1）使用感测前和感觉HTPC的一系列研究。感觉细胞的细胞和分子表征包括一个综合的分泌谱，以定义与感应相关的分泌表型（SASP）和分析体外衰老的后果。在细胞培养研究中将探讨改变秘书因素的行为。功能测定包括收缩性评估和平滑肌标记和干细胞特征的检查。 （2）对年轻人和健康但健康的非人类隐私（Common Marmoset Monkey（Callithrix jacchus）和Rhesus Monkey（Macaca Mulatta）的老年人和健康的非人类隐私（Macaca Mulatta）的实证样品的互补研究）。这些翻译的动物模型在很大程度上排除了混淆健康问题，并使我们能够区分睾丸的年龄和疾病相关的变化，这在人类中并非完全可能。涉及整个转录组分析和实证形态的研究将通过对年轻成人和旧Callithrix Jacchus的孤立PTC进行研究来完成。我们预计我们项目的结果将阐明验证衰老的机制。获得的见解可能会导致新颖的方法来拦截衰老的验证后果。

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.