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Schlatt S.,Institute of Reproductive and Regenerative Biology | Schlatt S.,University of Pittsburgh | Westernstroer B.,University of Pittsburgh | Gassei K.,University of Pittsburgh | And 2 more authors.
Biology of Reproduction | Year: 2010

Immature testicular tissue of a wide variety of mammalian species continues growth and maturation when ectopically grafted under the dorsal skin of adult nude mouse recipients. Tissues from most donor species fully mature, exhibiting complete spermatogenesis within months. The connection to the recipient's vascular system is mandatory for graft development, and failure of vascularization leads to necrosis in the grafted tissue. In the present study, we analyze to what extent 1) the xenografted immature donor tissue and 2) the recipient's cells and tissues contribute to the functional recovery of a "testicular xenograft." We address whether recipient cells migrate into the testicular parenchyma and whether the circulatory connection between the donor testicular tissue and the recipient is established by ingrowing host or outgrowing donor blood vessels. Although this issue has been repeatedly discussed in previous xenografting studies, so far it has not been possible to unequivocally distinguish between donor and recipient tissues and thus to identify the mechanisms by which the circulatory connection is established. To facilitate the distinction of donor and recipient tissues, herein we used immature green fluorescent protein-positive rat testes as donor tissues and adult nude mice as graft recipients. At the time of graft recovery, donor tissues could be easily identified by the GFP expression in these tissues, allowing us to distinguish donor-and recipient-derived blood vessels. We conclude that the circulatory connection between graft and host is established by a combination of outgrowing small capillaries from the donor tissue and formation of larger vessels by the host, which connect the graft to subcutaneous blood vessels. © 2010 by the Society for the Study of Reproduction, Inc.

Brune M.,University of Heidelberg | Adams C.,Institute of Reproductive and Regenerative Biology | Gromoll J.,Institute of Reproductive and Regenerative Biology
Molecular and Cellular Endocrinology | Year: 2010

Follicle-stimulating hormone (FSH) is essential for primate reproduction and acts via the FSH-receptor (FSHR). Although the FSHR expression is highly cell-specific, knowledge of the FSHR promoter and its transcriptional regulation is very limited. We applied a comparative genomic approach of important primate lineages to characterize the FSHR core promoter region. The core promoter sequences of the human and different primate species display significant variations in species-specific promoter activities shown by relative luciferase activity (RLA), ranging from 0.7-fold in the bonobo up to 3.5-fold in the chimpanzee compared to human. Comparison of the core promoter sequences revealed only very few interspecies nucleotide mismatches. Sequence homology ranged between 88% in the marmoset to 98% in chimpanzee compared to human FSHR. Mutagenesis of a single nucleotide next to a putative E-twenty-six (ETS) binding site caused a significant increase for human and a decrease for chimpanzee in RLA. An accompanying change in the pattern of protein binding to mutated human and chimpanzee ETS binding sites was demonstrated by EMSA, confirming a hitherto unknown role for this ETS binding site in FSHR promoter activity. Although the FSHR promoter displays a great sequence homology among primates, single nucleotide changes have significant impact on FSHR promoter activity. Thus promoter studies of closely related species could yield important insights into different regulatory promoter elements caused by nucleotide substitutions. © 2009 Elsevier Ireland Ltd. All rights reserved.

Westernstroer B.,Institute of Reproductive and Regenerative Biology | Langenstroth D.,Institute of Reproductive and Regenerative Biology | Troppmann B.,Institute of Reproductive and Regenerative Biology | Redmann K.,Institute of Reproductive and Regenerative Biology | And 5 more authors.
Cell and Tissue Research | Year: 2015

The chemokine receptor CXCR7 interacts with the chemokines CXCL11 and CXCL12. During development, this ligand receptor system (C-X-C) provokes cell-type-specific responses in terms of migration, adhesion or ligand sequestration. It is active in zebrafish and rodents but no data are available for its presence or function in primate testes. Real-time quantitative polymerase chain reaction was performed in monkeys to detect CXCL11, CXCL12 and CXCR7. At the protein level, CXCL12 and CXCR7 were localized in the testes of the marmoset (Callitrix jacchus) whereas CXCR7 patterns were determined for various stages in human testes. Morphometry and flow cytometry were applied to quantify CXCR7-positive cells in monkeys. Transcript levels and protein expression of CXCR7 were detectable throughout testicular development. In both species, CXCR7 protein expression was restricted to premeiotic germ cells. In immature marmoset testes, 69.9 % ± 9 % of the total germ cell population were labelled for CXCR7, whereas in the adult, 4.7 % ± 2.7 % were positive for CXCR7. CXCL12 mRNA was detectable in all developmental stages in marmosets. The CXCL12 protein was exclusively localized to Sertoli cells. This pattern of CXCL12/CXCR7 indicates their involvement in regulatory processes that possibly orchestrate the interaction between undifferentiated germ cells and Sertoli cells. © 2015, Springer-Verlag Berlin Heidelberg.

Schneider F.,Institute of Reproductive and Regenerative Biology | Neuhaus N.,Institute of Reproductive and Regenerative Biology | Wistuba J.,Institute of Reproductive and Regenerative Biology | Hess J.,Universitatsklinikum Essen | And 3 more authors.
Journal of Sexual Medicine | Year: 2015

Introduction: Cross-sex hormone treatment of gender dysphoria (GD) patients changing from male to female a prerequisite for sex reassignment. For initial physical adaptation, a combined treatment of anti-androgens and estrogens is used. Provided that patients fulfill specific criteria, sex reassignment surgery (SRS) presents the final step toward physical adaptation. However, systematic studies analyzing effects of hormone treatment regimens are lacking. Aim: The aim of this study was to compare the effects of three different hormonal treatment strategies regarding endocrinological parameters and testicular histology. Methods: Testicular tissues were obtained in a multicenter study from 108 patients on the day of SRS from three clinics following different treatment strategies. Patients either discontinued treatment 6 weeks (clinic A) or 2 weeks (clinic B) prior to SRS or not at all (clinic C). Testicular tissues, ethylenediaminetetraacetic acid blood and questionnaires were obtained on the day of SRS. Main Outcome Measures: Blood hormone and intratesticular testosterone (ITT) levels were measured. Testicular weight and histology were evaluated and the percentage of luteinizing hormone/choriogonadotropin receptor (LHCGR) positive cells was determined. Results: According to the questionnaires, patients showed desired phenotypical changes including breast growth (75%) and smooth skin (32%). While patients from clinics A and B presented with rather virilized hormonal levels, patients from clinic C showed generally feminized blood serum levels. Histological evaluation revealed highly heterogeneous results with about 24% of patients presenting with qualitatively normal spermatogenesis. In accordance with serum endocrine profile, ITT levels were lowest in clinic C and correlated with testosterone and free testosterone, but not with the spermatogenic state. The percentage of LHCGR-positive cells and ITT levels did not correlate. Conclusion: Only patients that did not discontinue hormonal treatment showed feminized blood levels on the day of SRS. The ones who stopped re-virilized quickly. Interestingly, testicular histology was highly heterogeneous irrespective of the treatment strategy, a phenomenon that requires further investigation. © 2015 International Society for Sexual Medicine.

Schlatt S.,Institute of Reproductive and Regenerative Biology | Schlatt S.,University of Pittsburgh | Gassei K.,University of Pittsburgh | Westernstroer B.,Institute of Reproductive and Regenerative Biology | And 3 more authors.
Endocrinology | Year: 2010

The hypothalamic-pituitary-gonadal (HPG) axis is involved in both the regulation of growth of the developing testis and in controlling spermatogenic and steroidogenic activity in the adult testis. Here, we develop a novel testicular xenografting model to examine to which degree testicular growth and function are controlled by intra-and extra testicular factors. Two or eight halves of neonatal Djungarian hamster testes were implanted into intact, hemicastrated, or castrated nude mouse recipients, and the development of the grafts under reduced or increased competition of testicular tissue was monitored and analyzed. We hypothesized that the outgrowth of the testicular grafts is influenced by the total amount of testicular tissue present in a host and that less testicular tissue in a host would result in more extended outgrowth of the grafts. Our results reveal that the hypothesis is wrong, because implanted hamster testis tissue irrespectively of the grafting condition grows to a similar size revealing an intrinsic mechanism for testicular growth. In contrast, similar size of seminal vesicle as bio-indicator of androgen levels in all hosts revealed that the steroidogenic activity is independent from the mass of testicular tissue and that steroid levels are extrinsically regulated by the recipient's HPG axis. We propose that the model of testicular xenografting provides highly valuable options to explore testicular growth and endocrine regulation of the HPG axis. Copyright © 2010 by The Endocrine Society.

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