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Jens Ehmcke Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, MWRI B301, 204 Craft Avenue, Pittsburgh, Pennsylvania 15213, USA

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Stefan Schlatt Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, MWRI B301, 204 Craft Avenue, Pittsburgh, Pennsylvania 15213, USA

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Fertility preservation in the male is routinely focused on sperm. In clinical and veterinary settings, cryopreservation of sperm is a widely used tool. However, the goals for male fertility preservation differ between experimental models, maintenance of livestock, conservation of rare species, and fertility protection in men. Therefore very different approaches exist, which are adapted to the specialized needs for each discipline. Novel tools for male fertility preservation are explored targeting immature germ cells in embryonic or immature testes. Many options might be developed to combine germline preservation and generation of sperm ex vivo leading to interesting new perspectives. This review highlights current and future options for male fertility preservation with a special focus on animal models and a consideration of the various disciplines in need of novel tools.

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Jens Ehmcke Department of Cell Biology and Physiology, Center for Research in Reproductive Physiology, University of Pittsburgh School of Medicine, W952 Biomedical Sciences Tower, 3500 Terrace Street, Pittsburgh, Pennsylvania 15261, USA

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Stefan Schlatt Department of Cell Biology and Physiology, Center for Research in Reproductive Physiology, University of Pittsburgh School of Medicine, W952 Biomedical Sciences Tower, 3500 Terrace Street, Pittsburgh, Pennsylvania 15261, USA

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We have recently described a revised scheme for spermatogonial expansion in non-human primates. We proposed that Apale-spermatogonia act as self-renewing progenitors and premeiotic germ cells are organized and divide as small clones. Here, we are revisiting the model described for man and propose a modified scheme for spermatogonial expansion. Our revised model shows high similarity to the scheme proposed for non-human primates and is in accordance with all previous and present data.

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Kathrin Gassei Department of Cell Biology and Physiology, Institute of Reproductive and Regenerative Biology, Center for Research in Reproductive Physiology, University of Pittsburgh School of Medicine, 3500 Terrace Street, Pittsburgh, Pennsylvania 15261, USA

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Jens Ehmcke Department of Cell Biology and Physiology, Institute of Reproductive and Regenerative Biology, Center for Research in Reproductive Physiology, University of Pittsburgh School of Medicine, 3500 Terrace Street, Pittsburgh, Pennsylvania 15261, USA
Department of Cell Biology and Physiology, Institute of Reproductive and Regenerative Biology, Center for Research in Reproductive Physiology, University of Pittsburgh School of Medicine, 3500 Terrace Street, Pittsburgh, Pennsylvania 15261, USA

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Stefan Schlatt Department of Cell Biology and Physiology, Institute of Reproductive and Regenerative Biology, Center for Research in Reproductive Physiology, University of Pittsburgh School of Medicine, 3500 Terrace Street, Pittsburgh, Pennsylvania 15261, USA
Department of Cell Biology and Physiology, Institute of Reproductive and Regenerative Biology, Center for Research in Reproductive Physiology, University of Pittsburgh School of Medicine, 3500 Terrace Street, Pittsburgh, Pennsylvania 15261, USA

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The first morphological sign of testicular differentiation is the formation of testis cords. Prior to cord formation, newly specified Sertoli cells establish adhesive junctions, and condensation of somatic cells along the surface epithelium of the genital ridge occurs. Here, we show that Sertoli cell aggregation is necessary for subsequent testis cord formation, and that neurotrophic tyrosine kinase receptors (NTRKs) regulate this process. In a three-dimensional cell culture assay, immature rat Sertoli cells aggregate to form large spherical aggregates (81.36±7.34 μm in diameter) in a highly organized, hexagonal arrangement (376.95±21.93 μm average distance between spherical aggregates). Exposure to NTRK inhibitors K252a and AG879 significantly disrupted Sertoli cell aggregation in a dose-dependent manner. Sertoli cells were prevented from establishing cell–cell contacts and from forming spherical aggregates. In vitro-derived spherical aggregates were xenografted into immunodeficient nude mice to investigate their developmental potential. In controls, seminiferous tubule-like structures showing polarized single-layered Sertoli cell epithelia, basement membranes, peritubular myoid cells surrounding the tubules, and lumen were observed in histological sections. By contrast, grafts from treatment groups were devoid of tubules and only few single Sertoli cells were present in xenografts after 4 weeks. Furthermore, the grafts were significantly smaller when Sertoli cell aggregation was disrupted by K252a in vitro (20.87 vs 6.63 mg; P<0.05). We conclude from these results that NTRK-regulated Sertoli–Sertoli cell contact is essential to the period of extensive growth and remodeling that occurs during testicular tubulogenesis, and our data indicate its potential function in fetal and prepubertal testis differentiation.

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Jens Ehmcke Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, W952 Biomedical Science Towers, 3500 Terrace Street, Pittsburgh 15261, Pennsylvania, USA

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Bhavika Joshi Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, W952 Biomedical Science Towers, 3500 Terrace Street, Pittsburgh 15261, Pennsylvania, USA

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Scott D Hergenrother Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, W952 Biomedical Science Towers, 3500 Terrace Street, Pittsburgh 15261, Pennsylvania, USA

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Stefan Schlatt Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, W952 Biomedical Science Towers, 3500 Terrace Street, Pittsburgh 15261, Pennsylvania, USA

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Testes in aging mammals undergo a variety of age-related changes, such as reduction of size, lower sperm output, an increase in abnormal forms of sperm, and endocrine malfunctions. It has been suggested that the spermatogenic defects are due to loss and dysfunction of spermatogonial stem cells as well as deterioration of the tubule microenvironment. In the present study, we explore the depletion and recovery of spermatogenesis in young (3 month) and old (12 month) mice exposed to cooling, X-irradiation (5 Gy) or cytotoxic treatment using Busulfan (40 mg/kg). We aim to determine a potential age-related change of vulnerability to gonadotoxic treatments by describing the intensity of spermatogenic depletion and the degree of spermatogenic recolonization with qualitative and quantitative parameters on organ weights and histological parameters at two time points (2 weeks, depletion; 6 weeks, recovery). Our data reveal specific acute effects of cooling on multinucleation of germ cells but no other severe injury. Irradiation and Busulfan-treatment exerted the expected depletional wave of germ cells leading to severe testicular injury and spermatogenic failure. The recovery of spermatogenesis occurred in both treatment groups and both age groups to a similar extent. We therefore noted no prominent age-related differences in spermatogenic depletion and recovery in any treatment group. We conclude that in both age groups, the remaining spermatogonial stem cells are capable to induce spermatogenic recovery and the aging tubule microenvironment at 1 year has not become more vulnerable to irradiation, Busulfan-treatment or testicular cooling.

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Steffi Werler
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Hannah Demond
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Oliver S Damm
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Jens Ehmcke Institute of Reproductive and Regenerative Biology, Central Animal Facility of the Faculty of Medicine, Institute for Anatomy and Cell Biology, Centre of Reproductive Medicine and Andrology, University of Muenster, Albert-Schweitzer-Campus 1 (D11), 48149 Muenster, Germany

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Ralf Middendorff Institute of Reproductive and Regenerative Biology, Central Animal Facility of the Faculty of Medicine, Institute for Anatomy and Cell Biology, Centre of Reproductive Medicine and Andrology, University of Muenster, Albert-Schweitzer-Campus 1 (D11), 48149 Muenster, Germany

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Jörg Gromoll
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Joachim Wistuba
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Klinefelter's syndrome is a male sex-chromosomal disorder (47,XXY), causing hypogonadism, cognitive and metabolic deficits. The majority of patients are infertile due to complete germ cell loss after puberty. As the depletion occurs during development, the possibilities to study the underlying causes in humans are limited. In this study, we used the 41,XXY* mouse model to characterise the germ line postnatally. We examined marker expression of testicular cells focusing on the spermatogonial stem cells (SSCs) and found that the number of germ cells was approximately reduced fivefold at day 1pp in the 41,XXY* mice, indicating the loss to start prenatally. Concurrently, immunohistochemical SSC markers LIN28A and PGP9.5 also showed decreased expression on day 1pp in the 41,XXY* mice (48.5 and 38.9% of all germ cells were positive), which dropped to 7.8 and 7.3% on 3dpp, and were no longer detectable on days 5 and 10pp respectively. The differences in PCNA-positive proliferating cells in XY* and XXY* mice dramatically increased towards day 10pp. The mRNA expression of the germ cell markers Lin28a (Lin28), Pou5f1 (Oct4), Utf1, Ddx4 (Vasa), Dazl, and Fapb1 (Sycp3) was reduced and the Lin28a regulating miRNAs were deregulated in the 41,XXY* mice. We suggest a model for the course of germ cell loss starting during the intrauterine period. Neonatally, SSC marker expression by the already lowered number of spermatogonia is reduced and continues fading during the first postnatal week, indicating the surviving cells of the SSC population to be disturbed in their stem cell characteristics. Subsequently, the entire germ line is then generally lost when entering meiosis.

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Joachim Wistuba Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Albert-Schweitzer-Campus 1, Building D11, 48129 Münster, Germany

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C Marc Luetjens Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Albert-Schweitzer-Campus 1, Building D11, 48129 Münster, Germany

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Jens Ehmcke Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Albert-Schweitzer-Campus 1, Building D11, 48129 Münster, Germany

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Klaus Redmann Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Albert-Schweitzer-Campus 1, Building D11, 48129 Münster, Germany

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Oliver S Damm Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Albert-Schweitzer-Campus 1, Building D11, 48129 Münster, Germany

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Antje Steinhoff Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Albert-Schweitzer-Campus 1, Building D11, 48129 Münster, Germany

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Reinhild Sandhowe-Klaverkamp Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Albert-Schweitzer-Campus 1, Building D11, 48129 Münster, Germany

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Eberhard Nieschlag Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Albert-Schweitzer-Campus 1, Building D11, 48129 Münster, Germany

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Manuela Simoni Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Albert-Schweitzer-Campus 1, Building D11, 48129 Münster, Germany

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Stefan Schlatt Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Albert-Schweitzer-Campus 1, Building D11, 48129 Münster, Germany

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Marmosets are used as preclinical model in reproductive research. In contrast to other primates, they display short gestation times rendering this species valid for exploration of effects on fertility. However, their peculiar endocrine regulation differs from a those of macaques and humans. We subjected male marmosets to previously clinically tested hormonal regimens that are known to effectively suppress spermatogenesis. Beside a control group, seven groups (each n=6) were investigated for different periods of up to 42 months: regimen I, (four groups) received testosterone undecanoate (TU) and norethisterone enanthate (NETE); regimen II, (two groups) received TU and NETE followed by NETE only; and regimen III, (one group) received NETE only. Testicular volume, cell ploidy and histology, endocrine changes and fertility were monitored weekly. TU and NETE and initial TU and NETE treatment followed by NETE failed to suppress spermatogenesis and fertility. Testicular volumes dropped, although spermatogenesis was only mildly affected; however, testicular cellular composition remained stable. Serum testosterone dropped when NETE was given alone but the animals remained fertile. Compared with controls, no significant changes were observed in sperm motility and fertility. Administration of TU and NETE affected testicular function only mildly, indicating that the regulatory role of chorionic gonadotrophin and testosterone on spermatogenesis is obviously limited and testicular function is maintained, although the endocrine axis is affected by the treatment. In conclusion, marmosets showed a different response to regimens of male contraception from macaques or men and have to be considered as a problematic model for preclinical trials of male hormonal contraception.

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