Defining prepubertal primate spermatogonial stem cells to address fertility preservation in prepubertal boys
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PROVIDER: PRJNA917768 | ENA |
REPOSITORIES: ENA
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Project description:Antineoplastic treatments for cancer and other non-malignant disorders can result in male long-term or permanent infertility by ablating spermatogonial stem cells (SSCs). Preserving the future fertility of prepubertal patients faced with this prospect cannot rely on sperm banking. SSC transplantation using testicular tissue harvested before sterilizing treatment is a promising approach for restoring fertility, but lack of exclusive biomarkers which can unequivocally identify prepubertal SSCs in any primate species limits the therapeutic potential. To address this, we performed single-cell RNA-seq on unselected testis cells from immature baboons and macaques and compared these cells with published data from pre-pubertal human germ cells functionally-defined mouse SSCs. We found discrete groups of human spermatogonia while baboon and rhesus spermatogonia appeared less heterogenous. Cross-species analysis revealed cell types analogous to human SSCs in baboon and rhesus germ cells, but comparison with mouse SSCs revealed significant differences with primate SSCs. Indeed, a core component of a human SSC gene expression signature was conserved in baboon and rhesus spermatogonia and absent from mouse SSCs. These results further resolve the identity of pre-pubertal human SSCs and define novel pathways that could be leveraged for advancing their selection and propagation in vitro.
2023-05-15 | GSE222105 | GEO
Project description: Not available
| S-EPMC6112575 | biostudies-literature
Project description:Spermatogonial stem cells are the foundation of spermatogenesis and as such can serve as a tool for the treatment of infertility in prepubertal cancer survivors. Spermatogonial stem cells are unique as they develop from primordial germ cells (PGCs), which colonize the developing tubules as immature SSC precursors. It has been controversial, when SSCs are maturing to an adult-like stem cell and recent research has found that prepubertal SSCs are actually metabolically distinct from adult SSCs until puberty. Sertoli cells picture a major part of the SSC niche and undergo drastic changes with puberty and polarize to compartmentalize the seminiferous epithelium with formation of tight junctions to a tight basal part where SSCs reside and an apical part with more differentiated stages of spermatogenesis. In the study were mapping the progression of Sertoli cells maturation events to the metabolic changes SSCs undergo during prepubertal development.
2023-02-24 | PXD037764 | Pride
Project description:Fertility preservation for male childhood cancer survivors not yet capable of producing mature spermatozoa, relies on experimental approaches such as testicular explant culture. Although the first steps in somatic maturation can be observed in human testicular explant cultures, germ cell depletion is a common obstacle. Hence, understanding the spermatogonial stem cell (SSC) niche environment and in particular, specific components such as the seminiferous basement membrane (BM) will allow progression of testicular explant cultures. Here, we revealed that the seminiferous BM is established from 6 weeks post conception with the expression of laminin alpha 1 (LAMA 1) and type IV collagen, which persist as key components throughout development. With prepubertal testicular explant culture we found that seminiferous LAMA 1 expression is disrupted and depleted with culture time correlating with germ cell loss. These findings highlight the importance of LAMA 1 for the human SSC niche and its sensitivity to culture conditions.
| S-EPMC7911157 | biostudies-literature
Project description:Protein arginine methyltransferase 1 (Prmt1) is known as the major Type-I protein arginine methyltransferase that deposits asymmetrical dimethylarginine (ADMA) in both histone and non-histone substrates. Nonetheless, how Prmt1 and its downstream signalling through substrate methylation function in the male germline development remains poorly understood. In this study, we discovered that Prmt1 is predominantly present in the spermatogonial population during mouse spermatogenesis. Using three Cre-mediated conditional Prmt1 knockout mouse lines, we observed that Prmt1 is essential for the maintenance of spermatogonial cells and Prmt1-deposited ADMA marks coordinate an inherent homeostasis among three types of substrate methylation. In conjunction with high-throughput Cut&Tag and modified mini-bulk Smart-seq2 analyses, we unveiled that Prmt1-mediated H4R3me2a mark enriched in the promoter region, together with other histone arginine methylations, drives a global transcriptomic landscape that maintains the regular gene expression and alternative splicing. Collectively, we provide the genetic evidence showing the essential role of Prmt1-deposited arginine methylation in the establishment of transcriptional homeostasis, and shed light on the methylarginine signalling pathway in orchestrating spermatogonial development in the mammalian germline.
2023-03-31 | GSE227857 | GEO
Project description:BackgroundHematological stem cell transplantation (HSCT) is an established method which has markedly increased the survival rate of hematologic malignancies since its introduction in the 1980's. The conditioning for HSCT has known gonadotoxic effects and often leads to premature loss of fertility. In this study we have prospectively followed a cohort of girls undergoing HSCT and studied the outcomes of fertility preservation treatments performed before or after HSCT, as well as the long-term reproductive outcome.MethodsIn this one-center prospective study, 39 girls counselled for fertility preservation prior to or after conditioning for HSCT for malignant or benign diseases at childhood or adolescence between 1990 and 2017 were included. The patients were presented with the option to undergo cryopreservation of ovarian tissue or oocytes depending on their age and the time available. Follicle counts of the ovarian tissue and number of oocytes collected before or after HSCT were compared between patients treated for benign and malignant diseases. Hormone measurements post HSCT treatment, including FSH and AMH, reproductive outcomes and overall survival until January 2021 were investigated.ResultsIn total, 34 girls and adolescents underwent fertility preservation before or after HSCT. Before HSCT, ovarian tissue was cryopreserved in 15 patients and two patients had oocytes preserved. Thirteen patients cryopreserved ovarian tissue after HSCT and seven patients returned to cryopreserve oocytes. Follicles were present in all tissue samples collected prior to HSCT, and in more than half of the samples collected post-HSCT. Half of the patients had spontaneous menarche or resumed menstruation post HSCT. Overall, 35 patients had survived at end of follow up and 7 patients had achieved parenthood.ConclusionsSince fertility loss is common following HSCT, fertility preservation should be offered to all patients. Fertility preservation treatments can be performed both before and after HSCT.Clinical trial registrationhttps://clinicaltrials.gov/show/NCT04602962, identifier NTC04602962.
| S-EPMC8278233 | biostudies-literature
Project description:The present study was undertaken to discover molecular markers in bovine cumulus cells predictive of oocyte competence and elucidate their functional significance. Differences in RNA transcript abundance in cumulus cells harvested from oocytes of adult versus prepubertal animals (model of poor oocyte quality) were identified by microarray analysis. Four genes of interest encoding for the lysosomal cysteine proteinases cathepsin B, S, K and Z and displaying greater transcript abundance in cumulus cells surrounding oocytes harvested from prepubertal animals were chosen for further investigation. Greater mRNA abundance for such genes in cumulus cells of prepubertal oocytes was confirmed by real time RT-PCR. Elevated transcript abundance for cathepsins B, S and Z was also observed in cumulus cells surrounding adult metaphase II oocytes that developed to the blastocyst stage at a low percentage following parthenogenetic activation, versus those that developed at a high percentage. Functional significance of cumulus cell cathepsin expression to oocyte competence was confirmed by treatment of cumulus oocyte complexes during in vitro oocyte maturation with a cell permeable cysteine proteinase (cathepsin) inhibitor. Inhibitor treatment decreased apoptotic nuclei in the cumulus layer and enhanced development of parthenogenetically activated and in vitro fertilized adult oocytes to the blastocyst stage. Stimulatory effects of inhibitor treatment during meiotic maturation on subsequent embryonic development were not observed when oocytes were matured in the absence of cumulus cells. Results support a functional role for cumulus cell cathepsins in compromised oocyte competence and suggest that cumulus cell cathepsin mRNA abundance may be predictive of oocyte quality. Keywords: Bovine, microarray, cDNA, cumulus cells Differences in RNA transcript abundance in cumulus cells harvested from oocytes of adult versus prepubertal animals (model of poor oocyte quality) were identified by microarray analysis. Total RNA from pools of cumulus cells (n = 4) collected from adult and prepubertal animals for microarray experiments was amplified. Two color microarray experiments were conducted using a bovine cDNA array containing expressed sequence tags (ESTs) representing approximately 15200 unique genes. Hybridizations were performed on duplicate slides (prepubertal versus adult) and incorporated a dye swap. The total number of slides used is eight.
2010-05-25 | E-GEOD-10819 | biostudies-arrayexpress
Project description:In vitro and in vivo aging of mouse spermatogonial stem cells alters stem cell function based on quantitative spermatogonial stem cell transplantation analyses. We used microarrays to identify differential gene expression in vitro and in vivo aged spermatogonial stem cells to identify potential causes of observed phenotypic differences in aged spermatogonial stem cell function. Spermatogonial stem cells were isolated from young and serial-transplanted aged mouse donors and cultured for short and long periods. Spermatogonial stem cells were isolated from cultures and subjected to microarray analysis to identify differential gene expression.
2011-02-04 | E-GEOD-27043 | biostudies-arrayexpress
Project description:The spermatogonial stem cells (SSCs) niche is critical for SSC maintenance and the subsequent spermatogenesis. Numerous reproductive hazards impair the SSC niche, thereby result in aberrant SSC self-renewal and male infertility. However, promising agents targeting the impaired SSC niche to promote SSC self-renewal are still limited. Here, we screen out and assess the effects of Lovastatin on the self-renewal of mouse spermatogonial stem cells (mSSCs). Mechanistically, Lovastatin promotes the self-renewal of mSSCs and inhibits its inflammation and apoptosis through the regulation of isoprenoid intermediates. Likewise, other statins exhibit similar effects on SSC self-renewal. Remarkably, the treatment by Lovastatin could promote the self-renewal of mSSCs in the male gonadotoxicity model generated by busulfan injection. Noteworthy, we demonstrate that Lovastatin could significantly enhance the self-renewal of in vitro cultured primate SSCs. Collectively, our findings uncover that lovastatin could promote the self-renewal of both murine and primate SSCs and have implications for the treatment of certain male infertility using small compounds.
2022-06-10 | GSE182897 | GEO
Project description:Antineoplastic treatments for cancer and other non-malignant disorders can result in long-term or permanent male infertility by ablating spermatogonial stem cells (SSCs). SSC transplantation using testicular tissue harvested before a sterilizing treatment is a promising approach for restoring male fertility in these cases, but a lack of exclusive biomarkers to unequivocally identify prepubertal SSCs limits their therapeutic potential. To address this, we performed single-cell RNA-seq on testis cells from immature baboons and macaques and compared these cells with published data from prepubertal human testis cells and functionally-defined mouse SSCs. While we found discrete groups of human spermatogonia, baboon and rhesus spermatogonia appeared less heterogenous. A cross-species analysis revealed cell types analogous to human SSCs in baboon and rhesus germ cells, but a comparison with mouse SSCs revealed significant differences with primate SSCs. Primate-specific SSC genes were enriched for components and regulators of the actin cytoskeleton and participate in cell-adhesion, which may explain why the culture conditions for rodent SSCs are not appropriate for primate SSCs. Furthermore, correlating the molecular definitions of human SSC, progenitor and differentiating spermatogonia with the histological definitions of Adark/Apale spermatogonia indicates that both SSCs and progenitor spermatogonia are Adark, while Apale spermatogonia appear biased towards differentiation. These results resolve the molecular identity of prepubertal human SSCs, define novel pathways that could be leveraged for advancing their selection and propagation in vitro, and confirm that the human SSC pool resides entirely within Adark spermatogonia.
| S-EPMC10002546 | biostudies-literature