Targeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models
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PROVIDER: PRJNA742072 | ENA |
REPOSITORIES: ENA
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Project description:Type 2 diabetes mellitus is one of the most prevalent metabolic diseases affecting multiple organs, including reproductive disorders in male diabetic patients. However, the molecular mechanisms that contribute to spermatogenesis dysfunction in diabetic patients have not yet been fully elucidated. Here, we performed Smart-seq2 to examine the transcriptome of diabetic patients' testis cells at single cell resolution including all major cell types of the testis. Intriguingly, whereas spermatogenesis appears largely preserved, the gene expression profiles of Sertoli cells and the blood-testis barrier (BTB) structure were dramatically impaired. Among the deregulated pathways, the Apelin (APLN) peptide /Apelin-receptor (APJ) axis was hyper-activated in diabetic patients. Mechanistically, APLN is produced locally by Sertoli cells upon high glucose treatment, which subsequently suppressed the production of carnitine and repressed the expression of cell adhesion genes in Sertoli cells. Together, these effects culminated in BTB structural dysfunction. Finally, using the small molecule APLN receptor antagonist, ML221, we show that blocking APLN/APJ significantly ameliorated the BTB damage and, importantly, improved functional spermatogenesis in diabetic db/db mice. We also translated and validated these findings in cultured human testis. Our findings identify the APLN/APJ axis as a promising therapeutic target to improve reproduction capacity in male diabetic patients.
2022-10-27 | GSE179080 | GEO
Project description:Cultivation of neonatal mouse testis tissue can induce spermatogenesis and produce fertile sperms. However, this in vitro spermatogenesis by the current organ culture method comes short in fully mimicking the in vivo counterpart, partly due to a lack of knowledge about the underlying molecular phenotypes. In this study, we investigated transcriptome of cultured testis tissues using microarray method. Principle component analysis of the transcriptome data revealed delay and/or arrest of spermatogenesis and immediate radical immune reactions in the cultured testis tissues. The delay/arrest of spermatogenesis occurred before and during early meiotic phase, resulting in inefficient progression of meiosis. The immune reaction, on the other hand, was drastic and overwhelming, in which TLR4-NF-kB signaling was speculated to be involved. Notably, treatment with TAK242, an inhibitor of TLR4-NF-kB signaling pathway, ameliorated the macrophage activation which otherwise would exacerbate the inflammation. The present study revealed for the first time the immense immune reaction in the cultured tissue by transcriptomic analysis, which could be a cause of the inefficiency of in vitro spermatogenesis.
2020-06-30 | GSE147982 | GEO
Project description:Studying spermatogenesis is the key to understanding the development mechanism of the yak reproductive system. Although N6-methyladenosine (m6A) RNA modification has been reported to regulate spermatogenesis and reproductive function in mammals, the molecular mechanism of m6A in yak testis development and spermatogenesis remains largely unknown. Therefore, we collected testicular tissue from junile and adult yaks, and found that the m6A level significantly increased after sexual maturity in yak. In MeRIP-seq, 1,702 hypermethylated peaks and 724 hypomethylated peaks were identified. The hypermethylated differentially methylated RNAs (DMRs) (CIB2, AK1, FOXJ2, PKDREJ, SLC9A3, and TOPAZ1) mainly regulated spermatogenesis, while the hypomethylated DMRs (BCL6, USP25, CD96, EPHA2, and TAF12) mainly participated in immune response. Functional enrichment analysis showed that DMRs were significantly enriched in the adherens junction, gap junction, and Wnt, PI3K, and mTOR signaling pathways, regulating cell development, spermatogenesis, and testicular endocrine function. The functional analysis of differentially expressed genes showed that they were involved in the biological processes of mitosis, meiosis, and flagellated sperm motility during sexual maturity of yak testis. We also screened the key regulatory factors of testis development and spermatogenesis by combined analysis, which included BRCA1, CREBBP, STAT3, and SMAD4. This study has important research value and practical guiding significance for yak genetic improvement, particularly in understanding the molecular mechanism and evolutionary dynamics of the progression of testis developmental stages in yaks.
2023-04-15 | GSE229363 | GEO
Project description:Genes have been identifed in mammalian testes ，and were essential for development of testis and spermatogenesis.
2017-07-21 | GSE101697 | GEO
Project description:Our experimental design includes samples at different time points during the first wave of spermatogenesis. Each time point corresponds to specific cell content in the testis. First time point is post natal day (PND) 7, when only somatic cells and spermatogonia are present in the testis. Thereafter additional cell types are present in selected samples in chronological order: PND 14 contains early spermatocytes, PND 17 late spermatocytes, PND 21 round spermatids and finally PND 28 elongating spermatids. Our results highlight differentially expressed genes and gene isoforms, which are important for correct sperm development and male fertility. In addition, functional analysis suggests a highly controlled gene expression pattern during the first wave of spermatogenesis. Transcriptome sequencing of the mouse testes at PND 7, 14, 17, 21 and 28 for analysis of differences in gene expression pattern during the first wave of spermatogenesis. In total 10 samples were analysed, replicates for each time point.
2013-04-29 | E-GEOD-39970 | biostudies-arrayexpress
Project description:Our experimental design includes samples at different time points during the first wave of spermatogenesis. Each time point corresponds to specific cell content in the testis. First time point is post natal day (PND) 7, when only somatic cells and spermatogonia are present in the testis. Thereafter additional cell types are present in selected samples in chronological order: PND 14 contains early spermatocytes, PND 17 late spermatocytes, PND 21 round spermatids and finally PND 28 elongating spermatids. Our results highlight differentially expressed genes and gene isoforms, which are important for correct sperm development and male fertility. In addition, functional analysis suggests a highly controlled gene expression pattern during the first wave of spermatogenesis.
2013-04-29 | GSE39970 | GEO
Project description:Continuous sperm production is not necessary for the survival of the organism, but is essential to maintain a species. The process of spermatogenesis is comprised of three phases: mitotic proliferation, meiosis, and spermiogenesis. To illuminate germline intrinsic and extrinsic programs, we performed single-cell RNA sequencing on ~35K cells from the adult mouse testis. This analysis provides a comprehensive molecular atlas of the testis, identifying both known and novel cell types. We demonstrate for the first time the continuous nature of germ cell differentiation, provide molecular signatures and subtype-specific molecular markers, and identify several novel candidate regulators of spermatogenesis. Finally, we demonstrate in vivo using spatial mapping that germ and somatic cell molecular subtypes correspond to previously defined histological cell types residing at different stages of seminiferous epithelial cycle. Taken together, our results unveil the complexity of the testis, and provide a global, unbiased roadmap of the in vivo gametogenesis program.
2018-08-24 | GSE112393 | GEO
Project description:Temporal study of the first wave of spermatogenesis in juvenile mouse testis and analysis of four germ cell deficient mouse models.<br> A series of purified testis cell-types (McCarrey libraries)constituting a focussed gene set was exploited to examine gene expression in prepubertal mouse testis. Testis RNA from C57/BL6J mice at various ages post partum was compared to a common control consisting of adult (8 week) testis RNA from the same strain(also corresponding to the last time-point).This generates a time course showing the activation of genes on the array across the first wave of spermatogenesis, which can then be correlated with the appearance of specific germ cell types, allowing assignation of unknown genes to differing cell types. <br> <br> Adult testis RNA from four different genetic models of infertility (XXSxrb, mshi, Bax -/-, bs) were compared to age- and strain-matched normal control testis RNA. These models possess different cellular complements within the testis, which can be interpreted within the framework established by the first wave analysis and used to refine the assignment of genes to cell types.
2006-08-10 | E-MEXP-571 | biostudies-arrayexpress
Project description:Spermatogenic cells express more alternatively spliced RNAs than most whole tissues; however, the regulation of these events remains unclear. Here we characterize the function of a testis-specific IQ motif containing H gene (Iqch), whose expression has been confirmed to be testis specific in all mammalian species analyzed yet its role remains elusive. Using a mutant mouse model, we found that Iqch is essential for the specific expression of RNA isoforms during spermatogenesis. Through immunohistochemistry of adult mouse testis, we noted that Iqch was localized in somatic and germ cells, including spermatogonia, spermatocytes and round spermatids. Further, Iqch was expressed mainly in the nucleus at the stages spermatocyte and spermatid, where IQCH appeared juxtaposed with SRRM2 and ERSP1, suggesting that interactions among these proteins regulate alternative splicing (AS). By RNA-seq, we noted that mutant Iqch produces alterations in gene expression, including the clear downregulation of testis-specific lncRNAs and protein coding genes at the spermatid stage, and AS modifications, principally increased intron retention, resulting in complete male infertility. Interestingly, the presence of WT Iqch allowed us to identify novel spliced transcripts, while mutant Iqch modified the expression and use of hundreds of RNA isoforms, favoring the expression of the canonical form. This suggests that Iqch is part of a splicing control mechanism, essential in germ cell biology. Our findings reveal the role of Iqch in spermatogenesis and provide clues to the molecular mechanisms controlling the expression of RNA isoforms, mainly in the last stages of spermatogenesis
2023-03-22 | GSE214201 | GEO
Project description:Hemicastration is unilateral orchiectomy to remove an injured testis, and may influence spermatogenesis. However, the underlying molecular mechanisms are poorly understood. Here, we monitored hemicastrated mice and found no significant difference of growth or testosterone (P > 0.05) compared with control. The genome-wide DNA methylation pattern of remaining testis were investigated by RRBS. Substantial genes harbored differentially methylated regions in gene bodies, and were enriched in process of protein binding and cell adhesion. Moreover, RNA-seq results indicated that 46 DEGs involved in meiotic cell cycle, synaptonemal complex assembly and spermatogenesis were upregulated in the hemicastration group, while 197 DEGs were downregulated, which were related to arachidonic acid metabolism. Integrative analysis revealed that PSMC3IP, which encodes a protein crucial for homologous recombination in spermatocytes, exhibited promoter hypomethylation and higher expression level in hemicastrated mice. Our results demonstrated that hemicastration-induced compensatory response maintained normal growth and fertility in mice.
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