Lovastatin Promotes the Self-renewal of Murine and Primate Spermatogonial Stem Cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA758256 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15650218_1.fastq.gz | Fastqsanger.gz | |||
| SRR15650218_2.fastq.gz | Fastqsanger.gz | |||
| SRR15650219_1.fastq.gz | Fastqsanger.gz | |||
| SRR15650219_2.fastq.gz | Fastqsanger.gz | |||
| SRR15650220_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
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:Chromodomain Helicase DNA-binding Domain 2 (CHD2), as a chromatin remodeling factor, was shown to be involved in the regulation of gene expression in embryonic development, neurodevelopment and myelopoiesis. However, its role in male germ cell development has not been elucidated. Here, we confirmed that CHD2 is abundantly expressed throughout the male germ cells with the highest expression in the spermatocytes of meiosis I. By constructing a heterozygous gene knockout mouse model of Chd2 (Chd2+/-), we demonstrated that CHD2 haploinsufficiency resulted in testicular developmental delay and increased rate of abnormal sperm in mice. DNA damage repair, synapsis and cell proliferation during spermatogenesis are impaired in Chd2+/- mice. In vitro experiments in C18-4 and GC-1 spg cells showed that CHD2 knockdown inhibits spermatogonial self-renewal. Mechanically, CHD2 maintained the enrichment of H3K4me3 in Ccnb1 and Ccnd2 promoter consequently promoting the transcription of Ccnb1 and Ccnd2. In addition, by interacting with cleavage stimulation factor CSTF3, CHD2 binds Oct4, Plzf mRNA and upregulates the expression of OCT4 and PLZF by improving mRNA stability. This is the first time to reveal the role and mechanism of CHD2 in maintaining spermatogonial self-renewal by promoting chromatin activity and mRNA stability in spermatogenesis.
2023-03-11 | PXD032277 | Pride
Project description:Reactive oxygen species (ROS) play critical roles in self-renewal division for various stem cell types. However, it remains unclear how ROS signals are integrated with selfrenewal machinery. Here we report that the MAPK14/MAPK7/BCL6B pathway creates a positive feedback loop to drive spermatogonial stem cell (SSC) self-renewal via ROS amplification. The activation of MAPK14 induced MAPK7 phosphorylation in cultured SSCs, and targeted deletion of Mapk14 or Mapk7 resulted in significant SSC deficiency after spermatogonial transplantation. The activation of this signaling pathway not only induced Nox1 but also increased ROS levels. Chemical screening of MAPK7 targets revealed many ROS-dependent spermatogonial transcription factors, of which BCL6B was found to initiate ROS production by increasing Nox1 expression via ETV5-induced nuclear translocation. Because hydrogen peroxide or Nox1 transfection also induced BCL6B nuclear translocation, our results suggest that BCL6B initiates and amplifies ROS signals to activate ROS-dependent spermatogonial transcription factors by forming a positive feedback loop.
2020-10-24 | GSE106103 | GEO
Project description:ROS amplification drives mouse spermatogonial stem cell self-renewal
| PRJNA415605 | ENA
Project description:Reactive oxygen species (ROS) play critical roles in self-renewal division for various stem cell types. However, it remains unclear how ROS signals are integrated with self-renewal machinery. Here we report that the MAPK14/MAPK7/BCL6B pathway creates a positive feedback loop to drive spermatogonial stem cell (SSC) self-renewal via ROS amplification. The activation of MAPK14 induced MAPK7 phosphorylation in cultured SSCs, and targeted deletion of Mapk14 or Mapk7 resulted in significant SSC deficiency after spermatogonial transplantation. The activation of this signaling pathway not only induced Nox1 but also increased ROS levels. Chemical screening of MAPK7 targets revealed many ROS-dependent spermatogonial transcription factors, of which BCL6B was found to initiate ROS production by increasing Nox1 expression via ETV5-induced nuclear translocation. Because hydrogen peroxide or Nox1 transfection also induced BCL6B nuclear translocation, our results suggest that BCL6B initiates and amplifies ROS signals to activate ROS-dependent spermatogonial transcription factors by forming a positive feedback loop.
2019-12-01 | GSE118191 | GEO
Project description:Chromodomain Helicase DNA-binding Domain 2 (CHD2), as a chromatin remodeling factor, was shown to be involved in the regulation of gene expression in embryonic development, neurodevelopment and myelopoiesis. However, its role in male germ cell development has not been elucidated. Here, we confirmed that CHD2 is abundantly expressed throughout the male germ cells with the highest expression in the spermatocytes of meiosis I. By constructing a heterozygous gene knockout mouse model of Chd2 (Chd2+/-), we demonstrated that CHD2 haploinsufficiency resulted in testicular developmental delay and increased rate of abnormal sperm in mice. DNA damage repair, synapsis and cell proliferation during spermatogenesis are impaired in Chd2+/- mice. In vitro experiments in C18-4 and GC-1 spg cells showed that CHD2 knockdown inhibits spermatogonial self-renewal. Mechanically, CHD2 maintained the enrichment of H3K4me3 in Ccnb1 and Ccnd2 promoter consequently promoting the transcription of Ccnb1 and Ccnd2. In addition, by interacting with cleavage stimulation factor CSTF3, CHD2 binds Oct4, Plzf mRNA and upregulates the expression of OCT4 and PLZF by improving mRNA stability. This is the first time to reveal the role and mechanism of CHD2 in maintaining spermatogonial self-renewal by promoting chromatin activity and mRNA stability in spermatogenesis.
2022-11-15 | GSE198581 | GEO
Project description:Spermatogonial stem cells undergo both self-renewal to maintain the stem cell population and differentiation to produce mature sperm. These processes are controlled by both stem cell-intrinsic and external niche factors. DOT1L, the sole H3K79 methyltransferase, is dispensable for mouse embryonic stem cell self-renewal but instead functions as a barrier to somatic cell reprogramming. Here we show that DOT1L is required for spermatogonial stem cell self-renewal. Mice lacking DOT1L in the germ cells show a failure in the maintenance of spermatogonial stem cells without a block in spermatogenic cell differentiation and thus a progressive loss of germ cells, leading to a Sertoli-cell-only syndrome. Chemical inhibition of DOT1L in cultured stem cells reduces the spermatogonial stem cell activity after transplantation. RNA-seq analysis reveals downregulation of Hoxc cluster genes in DOT1L-inhibited spermatogonia stem cells. Single cell RNA-seq analysis demonstrates that inhibition of DOT1L sequesters spermatogonial stem cells in a primitive state and prevents them from transitioning to a progenitor state. These results identify a new function for DOT1L in adult stem cells and provides a paradigm for regulation of spermatogonial stem cell self-renewal. Self-renewal of spermatogonial stem cells is vital to life-long production of male gametes and thus fertility. However, the underlying mechanisms remain enigmatic. Here, we show that DOT1L, the sole H3K79 methyltransferase, is required for spermatogonial stem cell self-renewal. Mice lacking DOT1L fail to maintain spermatogonial stem cells, characterized by a sequential loss of germ cells from spermatogonia to spermatids and ultimately a Sertoli-cell-only syndrome. Inhibition of DOT1L reduces the stem cell activity after transplantation, prevents spermatogonial stem cells from transitioning to a progenitor state, and sequesters them in a primitive state. Furthermore, DOT1L promotes expression of the fate-determining HoxC transcription factors in spermatogonial stem cells. Our findings identify an essential function for DOT1L in adult stem cells and provide an epigenetic paradigm for regulation of spermatogonial stem cells.
2022-06-30 | GSE193575 | GEO
Project description:CHD2 maintains spermatogonial self-renewal by promoting chromatin activity and mRNA stability
| PRJNA816070 | ENA
Project description:Testis immune privilege is thought to be mediated by somatic cells. However, it is not strong enough to protect allogeneic spermatogonial stem cells (SSCs) transplanted into the seminiferous tubules. Here we report successful production of allogeneic offspring by inducing PD-L1 in SSCs. Activation of self-renewal division induced PD-L1 and B7-H3 expression in cultured SSCs, which produced sperm after allogeneic transplantation. While B7-H3 depletion did not influence colonization, PD-L1 depletion prevented donor-derived spermatogenesis. PD-L1 expression was induced by BCL6B via reactive oxygen species (ROS) generation, suggesting that self-renewal stimulation confers immune privilege by ROS. In contrast, reduced ROS or Mapk14 deficiency downregulated PD-L1 expression. Allogeneic offspring were produced by SSC transplantation into congenitally infertile mice and busulfan-treated wild-type mice. Therefore, SSCs can escape rejection when their self-renewal division is stimulated.
2022-04-11 | GSE129658 | GEO
Project description:Testis immune privilege is thought to be mediated by somatic cells. However, it is not strong enough to protect allogeneic spermatogonial stem cells (SSCs) transplanted into the seminiferous tubules. Here we report successful production of allogeneic offspring by inducing PD-L1 in SSCs. Activation of self-renewal division induced PD-L1 and B7-H3 expression in cultured SSCs, which produced sperm after allogeneic transplantation. While B7-H3 depletion did not influence colonization, PD-L1 depletion prevented donor-derived spermatogenesis. PD-L1 expression was induced by BCL6B via reactive oxygen species (ROS) generation, suggesting that self-renewal stimulation confers immune privilege by ROS. In contrast, reduced ROS or Mapk14 deficiency downregulated PD-L1 expression. Allogeneic offspring were produced by SSC transplantation into congenitally infertile mice and busulfan-treated wild-type mice. Therefore, SSCs can escape rejection when their self-renewal division is stimulated.
2022-04-11 | GSE129546 | GEO