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Maintenance of adult tissues depends on stem cell self-renewal in local niches. Spermatogonial stem cells (SSC) are germline adult stem cells necessary for spermatogenesis and fertility. We show that testicular endothelial cells (TECs) are part of the SSC niche producing glial cell line-derived neurotrophic factor (GDNF) and other factors to support human and mouse SSCs in long-term culture. We demonstrate that FGF-2 binding to FGFR1 on TECs activates the calcineurin pathway to produce GDNF. Comparison of the TEC secretome to lung and liver endothelial cells identified 5 factors sufficient for long-term maintenance of human and mouse SSC colonies in feeder-free cultures. Male cancer survivors after chemotherapy are often infertile since SSCs are highly susceptible to cytotoxic injury. Transplantation of TECs alone restores spermatogenesis in mice after chemotherapy-induced depletion of SSCs. Identifying TECs as a niche population necessary for SSC self-renewal may facilitate fertility preservation for prepubertal boys diagnosed with cancer. Self-renewal of spermatogonial stem cells (SSC) is necessary for spermatogenesis and male fertility. Here the authors identify testicular endothelial cells (TECs) as a source of 5 key growth factors for self-renewal and expansion of human and mouse SSCs.

In the human testis, beginning at [almost equal to]2 months of age, gonocytes are replaced by adult dark (Ad) and pale (Ap) spermatogonia that make up the spermatogonial stem cell (SSC) pool. In mice, the SSC pool arises from gonocytes [almost equal to]6 days after birth. During puberty in both species, complete spermatogenesis is established by cells that differentiate from SSCs. Essentially pure populations of prepubertal human spermatogonia and mouse gonocytes were selected from testis biopsies and validated by confirming the presence of specific marker proteins in cells. Stem cell potential of germ cells was demonstrated by transplantation to mouse testes, following which the cells migrated to the basement membrane of the seminiferous tubule and were maintained similar to SSCs. Differential gene expression profiles generated between germ cells and testis somatic cells demonstrated that expression of genes previously identified as SSC and spermatogonial-specific markers (e.g., zinc-finger and BTB-domain containing 16, ZBTB16) was greatly elevated in both human spermatogonia and mouse gonocytes compared to somatic cells. Several genes were expressed at significantly higher levels in germ cells of both species. Most importantly, genes known to be essential for mouse SSC self-renewal (e.g., Ret proto-oncogene, Ret; GDNF-family receptor α1, Gfrα1; and B-cell CLL/lymphoma 6, member B, Bcl6b) were more highly expressed in both prepubertal human spermatogonia and mouse gonocytes than in somatic cells. The results indicate remarkable conservation of gene expression, notably for self-renewal genes, in these prepubertal germline cells between two species that diverged phylogenetically [almost equal to]75 million years ago.

Fertility preservation is an essential consideration of cancer management. Katz et al . outline the issues related to infertility for both prepubertal and postpubertal male patients with cancer and review the currently available approaches of fertility preservation. Experimental strategies that are under investigation for fertility preservation both before and after cancer treatment are also discussed. With the increasing number of patients surviving cancer, there is increasing interest in long-term quality of life, especially with respect to cancer-related infertility. Although infertility most commonly occurs as the result of treatment with gonadotoxic agents, it can also manifest before treatment has commenced. Current fertility preservation strategies for the postpubertal male patient with cancer focus on sperm cryopreservation before therapy. Sperm acquisition techniques should be discussed with the patient as early as possible, by either an oncologist or a specialist in male reproduction. For patients rendered infertile by cancer treatment who did not cryopreserve sperm beforehand, there are no techniques currently available to restore fertility. For the prepubertal male patient, cryopreservation of sperm is impossible. However, emerging research—primarily in animal models—into promising fertility preservation and restoration strategies might provide a clinical solution in the future. Advances in the protection and cryopreservation of spermatogonial stem cells (SSCs) might translate into clinical options for fertility preservation before treatment. Restoring fertility after treatment might also be possible via SSC autotransplantation or in vitro maturation of SSCs. Before any of these techniques become clinically viable, a number of scientific, logistical and ethical issues will need to be resolved. Key Points Infertility related to cancer is a major issue for many cancer survivors and should be discussed as early as possible during treatment planning Impairment of fertility related to cancer can manifest before, during or after treatment Existing fertility preservation strategies for men focus on acquiring sperm for cryopreservation before therapy; patients rendered infertile by cancer treatments who did not cryopreserve sperm beforehand are unable to father a biological child Promising advances in spermatogonial stem cell research might lead to future fertility preservation and restoration options for male patients with cancer A number of scientific, logistical and ethical barriers might need to be overcome before investigational fertility preservation strategies can be used clinically, especially for prepubertal patients Development of, and adherence to, clinical care pathways, education of oncological health-care providers and involvement of male reproductive specialists should be included in the management of infertility in male patients with cancer

Background Copy number variation (CNV) is a potential contributing factor to many genetic diseases. Here we investigated the potential association of CNV with nonsyndromic cryptorchidism, the most common male congenital genitourinary defect, in a Caucasian population. Methods Genome wide genotyping were performed in 559 cases and 1772 controls (Group 1) using Illumina HumanHap550 v1, HumanHap550 v3 or Human610-Quad platforms and in 353 cases and 1149 controls (Group 2) using the Illumina Human OmniExpress 12v1 or Human OmniExpress 12v1-1. Signal intensity data including log R ratio (LRR) and B allele frequency (BAF) for each single nucleotide polymorphism (SNP) were used for CNV detection using PennCNV software. After sample quality control, gene- and CNV-based association tests were performed using cleaned data from Group 1 (493 cases and 1586 controls) and Group 2 (307 cases and 1102 controls) using ParseCNV software. Meta-analysis was performed using gene-based test results as input to identify significant genes, and CNVs in or around significant genes were identified in CNV-based association test results. Called CNVs passing quality control and signal intensity visualization examination were considered for validation using TaqMan CNV assays and QuantStudio® 3D Digital PCR System. Results The meta-analysis identified 373 genome wide significant ( p  < 5X10 −4 ) genes/loci including 49 genes/loci with deletions and 324 with duplications. Among them, 17 genes with deletion and 1 gene with duplication were identified in CNV-based association results in both Group 1 and Group 2. Only 2 genes ( NUCB2 and UPF2 ) containing deletions passed CNV quality control in both groups and signal intensity visualization examination, but laboratory validation failed to verify these deletions. Conclusions Our data do not support that structural variation is a major cause of nonsyndromic cryptorchidism.

Normal human sexual development occurs in a highly regulated process that comprises three distinct phases: establishment of chromosomal sex, development of the sex-specific gonads and phenotypic differentiation of the internal ductal anatomy and external genitalia. The latter two phases are mediated by specific hormonal effector molecules, including anti-Müllerian hormone and testosterone, and their dysregulation often leads to the development of a phenotypic disorder of sexual differentiation. This review describes the hormonal mediators that are involved in sexual development and the disorders of sexual differentiation that arise from their dysfunction.