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The Human Testis Cell Atlas via Single-cell RNA-seq (Infant scRNA-seq data set)

ABSTRACT: Human adult spermatogenesis involves a balance of spermatogonial stem cell self renewal and differentiation, alongside complex germline-niche interactions. To better understand, we performed single cell RNA sequencing of ~7000 testis cells from three healthy men of peak reproductive age. Our analyses revealed multiple distinctive transcriptional ‘states’ of self-renewing and differentiating spermatogonia, the cellular stages of gametogenesis, five niche cells (Leydig, Myoid, Sertoli, Endothelial, macrophage) and insights into germline-niche communication. Spermatogenesis was reconstructed computationally, which identified sequential coding, noncoding, and repeat-element transcriptional signatures. A new, developmentally early and likely quiescent spermatogonial state is identified (GFRA1-/ETV5-/ID4+/UTF1+/FGFR3+). Notably, certain epigenetic features combined with nascent transcription analyses suggest considerable plasticity within certain spermatogonial populations/states. Key findings were validated via RNA and protein staining. Taken together, we provided the first “Cell Atlas” of the adult human testis, and provide multiple new insights into germ cell development and germ cell – niche interaction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120506 | GEO | 2018/10/15

REPOSITORIES: GEO

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The Human Testis Cell Atlas via Single-cell RNA-seq (KIT+ spermatogonia ATAC-seq data set)

Project description:Human adult spermatogenesis involves a balance of spermatogonial stem cell self renewal and differentiation, alongside complex germline-niche interactions. To better understand, we performed single cell RNA sequencing of ~7000 testis cells from three healthy men of peak reproductive age. Our analyses revealed multiple distinctive transcriptional ‘states’ of self-renewing and differentiating spermatogonia, the cellular stages of gametogenesis, five niche cells (Leydig, Myoid, Sertoli, Endothelial, macrophage) and insights into germline-niche communication. Spermatogenesis was reconstructed computationally, which identified sequential coding, noncoding, and repeat-element transcriptional signatures. A new, developmentally early and likely quiescent spermatogonial state is identified (GFRA1-/ETV5-/ID4+/UTF1+/FGFR3+). Notably, certain epigenetic features combined with nascent transcription analyses suggest considerable plasticity within certain spermatogonial populations/states. Key findings were validated via RNA and protein staining. Taken together, we provided the first “Cell Atlas” of the adult human testis, and provide multiple new insights into germ cell development and germ cell – niche interaction.

2018-10-15 | GSE120507 | GEO

The Human Testis Cell Atlas via Single-cell RNA-seq (Healthy men scRNA-seq data set)

2018-10-15 | GSE112013 | GEO

EGR4-dependent decrease of UTF1 is associated with failure to reserve spermatogonial stem cells in infertile men

Project description:Despite the high incidence of male infertility, about 70% of infertile men do not receive a causative diagnosis. To gain insights into the regulatory mechanisms governing human germ cell function in normal and impaired spermatogenesis (crypto group), we combined single cell RNA sequencing (>30.000 cells), proteome, and histomorphometric analyses of testicular tissues. We found major alterations in the crypto spermatogonial compartment with increased numbers of the most undifferentiated spermatogonia (PIWIL4+ State 0 cells). We also observed a transcriptional switch within the spermatogonial compartment driven by the increased and prolonged expression of the transcription factor EGR4. Intriguingly, EGR4-regulated genes included the chromatin-associated transcriptional repressor UTF1, which was downregulated. Histomorphometrical analyses showed that these transcriptional changes were mirrored at the protein level and accompanied by a change in the chromatin structure of spermatogonia. This resulted in a reduction of Adark spermatogonia - characterized by tightly compacted chromatin and serving as reserve stem cells. These findings suggest that crypto patients are at a disadvantage especially in cases of gonadotoxic damage as they have less cells to help repopulate the testis. We hypothesize that the more relaxed chromatin status of spermatogonia is dependent on decreased UTF1 expression caused by EGR4 activation. These identified regulators of the spermatogonial compartment will be highly interesting targets to uncover genetic causes of male infertility.

2021-11-02 | PXD023979 | Pride

Identification of Glucocorticoid-Induced Leucine Zipper (Gilz) gene targets in undifferentiated spermatogonia

Project description:Sustained spermatogenesis in adult males and recovery of fertility following germ cell depletion are dependent on undifferentiated spermatogonia with self-renewal potential. We have previously demonstrated a critical cell-autonomous role for Gilz in spermatogonial stem cell maintainance and spermatogenesis. To identify genes regulated by Gilz in the male germline, we have isolated undifferentiated spermatogonial cells from tamoxifen treated Gilzflox/flox (Control) and Gilzflox/flox UBC-CreER (TAM-KO) mice that will allow identification of genes mis-expressed upon loss of GILZ.

2018-08-24 | GSE107893 | GEO

Testis single-cell RNA-sequencing in the cynomolgus macaque reveals conserved transcriptional profiles during mammalian spermatogenesis

Project description:Spermatogenesis in mammals is a complex and highly orchestrated process, which involves the differentiation of diploid (2n-DNA content) spermatogonia into haploid (n) sperm. This process begins with spermatogonia, a niche of stem cells, which drive this process. Spermatogonial stem cells (SSCs) undergo mitotic self-renewal to maintain this niche, while sub-populations of spermatogonia progressively undergo differentiation and later gain competence to initiate meiosis and form sperm. SSCs undergo extensive chromatin remodelling and major morphological changes, while maintaining genome integrity and parental imprints. To study this in greater detail we performed single-cell RNA sequencing of spermatogenic cells derived from the testis of the non-human primate Macaca fascicularis.

2020-08-13 | E-MTAB-8979 | biostudies-arrayexpress

Protein composition of the extracellular matrix in idiopathic germ cell aplasia

Project description:The somatic microenvironment supports spermatogonial stem cell differentiation into sperm. Extracellular matrix (ECM) plays multiple roles in the stem cell niche, including self-renewal, proliferation, differentiation and survival of spermatogonial cells. The pathophysiology of male infertility might be representative of a progressive degenerative process of the testicular tissue, including ECM, rather than a defective genetic background, thus outlining the existence of chronic etiological agents/pathways. In this context, we sought to identify potential causative factors responsible for a number of modifications of the testicular somatic microenvironment associated with idiopathic germ cell aplasia in human beings. Proteomic analysis of the decellularized ECM was performed to study testis parenchyma from 10 idiopathic non-obstructive azoospermic (iNOA) men, dichotomized according to positive sperm retrieval versus germ cell aplasia. Germ cell aplasia was characterized by an increased nuclear distribution of the retinoic acid receptor in Sertoli cells which was associated with decreased expression of the ECM markers, Nidogen-2 and Heparan sulfate proteoglycan-2. Decreased levels of the interstitial matrisome associated Factor IX and its regulator VKORC1 were instead coupled with decreased signaling of vitamin K in Leydig cells. This study identified pathogenetic signature of the somatic testicular microenvironment and provide mechanistic insights into the molecular determinants of human idiopathic germ cell aplasia.

2019-01-07 | PXD011817 | Pride

Lovastatin Promotes the Self-renewal of Murine and Primate Spermatogonial Stem Cells

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

Molecular and cellular design of ovotestis development

Project description:Ovotestis often occurs in intersex individuals under certain pathological and physiological conditions. However, how ovotestis is formed remains unknown. Here, we report the first comprehensive single-cell developmental atlas of the model fish ovotestis. We provide an overview of ovotestis cell identities and a roadmap of germline, niche, and stem cell development in ovotestis by cell lineage reconstruction and a uniform manifold approximation and projection. We identify common progenitors of germline stem cells with two states, which reveal their bipotential nature to differentiate into both spermatogonial stem cells and female germline stem cells. Moreover, we found that ovotestis infertility was caused by developmental defects in oogenesis owing to dynamic autophagic degradation in female germline cells, and in spermatogenesis due to deficiency of histone-to-protamine replacement in spermatid differentiation. Notably, signaling pathways in gonadal niche cells and their interaction with germline cells synergistically determined cell fates of both male and female germlines in ovotestis. Overall, we reveal a cellular fate map of germline and niche cell development that shapes cell differentiation directions of ovotestis, and provide novel insights into ovotestis development.

2021-04-21 | GSE153961 | GEO

CHD2 maintains spermatogonial self-renewal by promoting chromatin activity and mRNA stability

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

Expression data of CD9 positive germ cells from young and aged Sprague Dawley germ cell specific GFP rats

Project description:Male fertility and testis function changes with age and so it was sought to determine if these changes are accompanied by changes in gene expression in the spermatogonial cells at the foundation of spermatogenesis A full genome microarray was used to determine if distinct pathways of genes were altered in expression in CD9-positive germ cells with age Testes from young (4 months) and aged (21 months) Sprague Dawley rats were subjected to dissociation to isolate a singel cell suspension of germ cells. These cells were used to isolate CD9 positive spermatogonial cells. RNA was isolated from these cells for hybridization on agilent miroarrays.

2013-12-05 | E-GEOD-50143 | biostudies-arrayexpress

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