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Project description:Because spermatogonial stem cells (SSCs) are virtually immortal by serial transplantation, SSC decrease in aged testes is considered to be caused by deteriorated microenvironment. Here we report cell-intrinsic mode of SSC aging. SSCs cultured for 5 years proliferate more actively than young SSCs and showed enhanced glycolytic activity but remain euploid and exhibited stable androgenetic imprinting patterns. Moreover, the aged SSCs kept constant SSC activity despite shortened telomeres. The increased proliferative activity of aged SSCs was caused by Wnt7b expression, which likely occurred due to decreased polycomb complex2 activity. Aberrant Wnt7b expression not only decreased reactive oxygen species levels and mitochondria activity but also stimulated glycolysis via c-jun N-terminal kinase (JNK) activation. Analysis of SSCs in Klotho aging mouse model also confirmed hyperactivation of JNK pathway and increased glycolysis. Therefore, not only SSC microenvironment but also intrinsic activation of Wnt7b-mediated glycolysis plays important roles in SSC aging.
2019-07-30 | GSE120775 | GEO
Project description:Because spermatogonial stem cells (SSCs) are virtually immortal by serial transplantation, SSC decrease in aged testes is considered to be caused by deteriorated microenvironment. Here we report cell-intrinsic mode of SSC aging. SSCs cultured for 5 years proliferate more actively than young SSCs and showed enhanced glycolytic activity but remain euploid and exhibited stable androgenetic imprinting patterns. Moreover, the aged SSCs kept constant SSC activity despite shortened telomeres. The increased proliferative activity of aged SSCs was caused by Wnt7b expression, which likely occurred due to decreased polycomb complex2 activity. Aberrant Wnt7b expression not only decreased reactive oxygen species levels and mitochondria activity but also stimulated glycolysis via c-jun N-terminal kinase (JNK) activation. Analysis of SSCs in Klotho aging mouse model also confirmed hyperactivation of JNK pathway and increased glycolysis. Therefore, not only SSC microenvironment but also intrinsic activation of Wnt7b-mediated glycolysis plays important roles in SSC aging.
2019-07-30 | GSE120777 | GEO
Project description:Aging of mouse spermatogonial stem cells by Wnt7b-Jnk pathway activation
| PRJNA494503 | ENA
Project description:Aging of mouse spermatogonial stem cells by Wnt7b-Jnk pathway activation [ChIP-seq]
| PRJNA494505 | ENA
Project description:Aging of mouse spermatogonial stem cells by Wnt7b-Jnk pathway activation [Bisulfite-seq]
| PRJNA494501 | ENA
Project description:Because spermatogonial stem cells (SSCs) are immortal by serial transplantation, SSC aging in intact testes is considered to be caused by a deteriorated microenvironment. Here, we report a cell-intrinsic mode of SSC aging by glycolysis activation. Using cultured SSCs, we found that aged SSCs proliferated more actively than young SSCs and showed enhanced glycolytic activity. Moreover, they remained euploid and exhibited stable androgenetic imprinting patterns with robust SSC activity despite having shortened telomeres. Aged SSCs showed increased Wnt7b expression, which was associated with decreased Polycomb complex 2 activity. Our results suggest that aberrant Wnt7b expression activated c-jun N-terminal kinase (JNK), which down-regulated mitochondria numbers by suppressing Ppargc1a Down-regulation of Ppargc1a probably decreased reactive oxygen species and enhanced glycolysis. Analyses of the Klotho-deficient aging mouse model and 2-y-old aged rats confirmed JNK hyperactivation and increased glycolysis. Therefore, not only microenvironment but also intrinsic activation of JNK-mediated glycolysis contributes to SSC aging.
| S-EPMC6697785 | biostudies-literature
Project description:The development of techniques to maintain the spermatogonial stem cell (SSC) in vivo and in vitro for extended periods essentially allows for the indefinite continuation of an individual germline. Recent evidence indicates that the aging of male reproductive function is due to failure of the SSC niche. SSCs are routinely cultured for 6 mo, and no apparent effect of culture over this period has been observed. To determine the effects of SSC aging, we utilized an in vitro culture system, followed by quantitative transplantation experiments. After culture for 6 mo, SSCs that had been aged in vivo for 1500 days had a slower proliferation rate than SSCs that were aged in vivo to 8 or 300 days. Examination of methylation patterns revealed no apparent difference in DNA methylation between SSCs that were aged 8, 300, or 1500 days before culture. Long-term culture periods resulted in a loss of stem cell potential without an obvious change in the visual appearance of the culture. DNA microarray analysis of in vivo- and in vitro-aged SSCs identified the differential expression of several genes important for SSC function, including B-cell CLL/lymphoma 6, member B (Bcl6b), Lim homeobox protein 1 (Lhx1), and thymus cell antigen 1, theta (Thy1). Collectively, these data indicate that, although both in vitro and in vivo aging are detrimental to SSC function, in vitro aging results in greater loss of function, potentially due to a decrease in core SSC self-renewal gene expression and an increase in germ cell differentiation gene expression.
| S-EPMC3062037 | biostudies-literature
Project description:Spermatogonial stem cells (SSCs) undergo self-renewal divisions to provide the foundation for spermatogenesis. Although Rb1 deficiency is reportedly essential for SSC self-renewal, its mechanism has remained unknown. Here we report that Rb1 is critical for cell cycle progression and protection of SSCs from DNA double-strand breaks (DSBs). Cultured SSCs depleted of Cdkn1b proliferated poorly and showed diminished expression of CDK4 and RB1, thereby leading to hypophosphorylation of RB1. Rb1 deficiency induced cell cycle arrest and apoptosis in cultured SSCs, which expressed markers for DNA DSBs. This DNA damage is caused by increased E2F1 activity, the depletion of which decreased DNA DSBs caused by Rb1 deficiency. Depletion of Cdkn1a and Bbc3, which were upregulated by Trp53, rescued Rb1-deficient cells from undergoing cell cycle arrest and apoptosis. These results suggest that the CDKN1B-RB1-E2F1 pathway is essential for SSC self-renewal and protects SSCs against genomic damage.
| S-EPMC4547988 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-03-16 | GSE130577 | GEO
Project description:Spermatogenesis is the process that involves the division and differentiation of spermatogonial stem cells into spermatozoa. However, the autocrine molecules and signaling pathways controlling their fate remain unknown. This study was designed to identify novel growth factors and signaling pathways that regulate proliferation, differentiation, and survival of spermatogonial stem/progenitor cells. To this end, we have for the first time explored the expression, function, and signaling pathway of Nodal, a member of the transforming growth factor-beta superfamily, in mouse spermatogonial stem/progenitor cells. We demonstrate that both Nodal and its receptors are present in these cells and in a spermatogonial stem/progenitor cell line (C18-4 cells), whereas Nodal is undetected in Sertoli cells or differentiated germ cells, as assayed by reverse transcription-polymerase chain reaction, Western blots, and immunocytochemistry. Nodal promotes proliferation of spermatogonial stem/progenitor cells and C18-4 cells, whereas Nodal receptor inhibitor SB431542 blocks their propagation as shown by proliferation and bromodeoxyuridine incorporation assays. Nodal knockdown by RNA interference results in a marked increase of cell apoptosis and a reduction of cell division as indicated by terminal deoxynucleotidyl transferase dUTP nick-end labeling and proliferation assays. Conversely, overexpression of Nodal leads to an increase of cell proliferation. Nodal activates Smad2/3 phosphorylation, Oct-4 transcription, cyclin D1, and cyclin E expression, whereas SB431542 completely abolishes their increase. Together, Nodal was identified as the first autocrine signaling molecule that promotes proliferation of mouse spermatogonial stem/progenitor cells via Smad2/3 and Oct-4 activation. This study thus provides novel and important insights into molecular mechanisms regulating proliferation and survival of spermatogonial stem/progenitor cells.
| S-EPMC3443855 | biostudies-literature