The role of testicular peritubular cells in human testicular ageing

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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.