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The emergence of multiple testicular cell lineages in human stem cell-derived testis-like organoids [RNA-Seq]

ABSTRACT: Reproductive development is a complex process orchestrated by precise gene expression and cellular interactions. Disruption to this process can result in Differences of Sex Development (DSDs) which occur in approximately 1-2% of live births. We have previously developed a protocol to differentiate human induced pluripotent stem cells (hiPSCs) into testis-like organoids as a model to study the molecular mechanisms underlying reproductive development and DSD. Here, we performed bulk and single-cell RNA sequencing on testis-like organoids to investigate their transcriptional landscape. Transcriptomic analysis revealed six cell clusters expressing markers associated with bipotential, early Sertoli, and testicular interstitial cells. To address the limited emergence of mature cell types, we generated a doxycycline-inducible NR5A1/SF1 hiPSC line, which successfully triggered the expression of Leydig cell markers upon overexpression. Our findings provide a comprehensive transcriptional profile of hiPSC-derived testis-like organoids, offering insights into human fetal gonadal development and a novel disease modelling system for DSDs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285050 | GEO | 2026/02/24

REPOSITORIES: GEO

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The emergence of multiple testicular cell lineages in human stem cell-derived testis-like organoids [scRNA-Seq]

Project description:Reproductive development is a complex process orchestrated by precise gene expression and cellular interactions. Disruption to this process can result in Differences of Sex Development (DSDs) which occur in approximately 1-2% of live births. We have previously developed a protocol to differentiate human induced pluripotent stem cells (hiPSCs) into testis-like organoids as a model to study the molecular mechanisms underlying reproductive development and DSD. Here, we performed bulk and single-cell RNA sequencing on testis-like organoids to investigate their transcriptional landscape. Transcriptomic analysis revealed six cell clusters expressing markers associated with bipotential, early Sertoli, and testicular interstitial cells. To address the limited emergence of mature cell types, we generated a doxycycline-inducible NR5A1/SF1 hiPSC line, which successfully triggered the expression of Leydig cell markers upon overexpression. Our findings provide a comprehensive transcriptional profile of hiPSC-derived testis-like organoids, offering insights into human fetal gonadal development and a novel disease modelling system for DSDs.

2026-02-24 | GSE285051 | GEO

Transcription profiling of Drosophila Hr39 mutant females reveals the sf1-related nuclear hormone receptor hr39 regulates Drosophila female reproductive tract development and function

Project description:The vertebrate nuclear hormone receptor steroidogenic factor 1 (SF1; NR5A1) controls reproductive development and regulates the transcription of steroid-modifying cytochrome P450 genes. We find that the SF1-related Drosophila nuclear hormone receptor HR39 is also essential for sexual development. In Hr39 mutant females, the sperm-storing spermathecae and glandular parovaria are absent or defective, causing sterility. Our results indicate that spermathecae and parovaria secrete reproductive tract proteins required for sperm maturation and function, like the mammalian epididymis and female reproductive tract. Hr39 controls the expression of specific cytochrome P450 genes and is required in females both to activate spermathecal secretion and repress male-specific courtship genes such as takeout. Thus, a pathway that, in vertebrates, controls sex-specific steroid hormone production, also mediates reproductive functions in an invertebrate. Our findings suggest that Drosophila can be used to model more aspects of mammalian reproductive biology than previously believed. Experiment Overall Design: Wild type and Hr39(04443) Spermathecae, Wild type and Hr39(04443) Reproductive Tract

2008-06-11 | E-GEOD-10264 | biostudies-arrayexpress

Dmrt1 (doublesex and mab-3 related transcription factor 1) conditional knockout expression analysis of P28 testes

Project description:Dmrt1 (doublesex and mab-3 related transcription factor 1) is a conserved transcriptional regulator of male differentiation required for testicular development in vertebrates. This study examines the result of conditional removal of Dmrt1 from Sertoli cells in P28 testis tissue. Testes from P28 Dmrt1 flox/flox mice were compared to testes from P28 Dmrt1 flox/flox mice with the Sertoli cell-specific Sf1 (Nr5a1; MGI:1346833) or Dhh (MGI:94891) promoters driving Cre expression.

2011-07-28 | E-GEOD-27261 | biostudies-arrayexpress

Project description:The vertebrate nuclear hormone receptor steroidogenic factor 1 (SF1; NR5A1) controls reproductive development and regulates the transcription of steroid-modifying cytochrome P450 genes. We find that the SF1-related Drosophila nuclear hormone receptor HR39 is also essential for sexual development. In Hr39 mutant females, the sperm-storing spermathecae and glandular parovaria are absent or defective, causing sterility. Our results indicate that spermathecae and parovaria secrete reproductive tract proteins required for sperm maturation and function, like the mammalian epididymis and female reproductive tract. Hr39 controls the expression of specific cytochrome P450 genes and is required in females both to activate spermathecal secretion and repress male-specific courtship genes such as takeout. Thus, a pathway that, in vertebrates, controls sex-specific steroid hormone production, also mediates reproductive functions in an invertebrate. Our findings suggest that Drosophila can be used to model more aspects of mammalian reproductive biology than previously believed. Keywords: mutant/wild-type comparison and tissue comparison

2008-04-26 | GSE10264 | GEO

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Project description:To examine the transcriptome of early testicular somatic cells during gonadogenesis at 12.5dpc RNA sequencing (RNA-Seq) was performed on murine primary testicular cell lineages isolated from the Sf1-eGFP line by FACS. The three main somatic cell lineages of the testis were isolated: the Sertoli cells which direct male development; the fetal Leydig cells (FLCs) that produce steroid hormones and virilise the XY individual and a heterogenous population of interstitial cells, some of which give rise to the adult Leydig cells (ALCs). This dataset provides a platform for exploring the biology of FLCs and understanding the role of these cells in testicular development and masculinization of the embryo, and a basis for targeted studies designed to identify causes of idiopathic XY DSD.

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Purification and transcriptomic analysis of mouse fetal Leydig cells reveals candidate genes for disorders of sex development

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Project description:Differences of sex development (DSD) and Testis Regression

| PRJNA982097 | ENA

Comparison of gene expression by RNA-seq in canine gonads from embryos at risk of XX Disorder of Sex Development (XX), male (XY) littermate controls, and age-matched female (XX) and male (XY) controls.

Project description:In a rare subtype of XX Disorder of Sex Development (DSD), individuals are negative for SRY, the testis determining factor on the Y chromosome, yet develop testes or ovotestes, and both of these phenotypes occur in the same family. This is a naturally occurring disorder in humans (Homo sapiens) and dogs (C. familiaris), and phenotypes in the canine XX DSD model are strikingly similar to those in this type of human XX DSD. The purposes of this study were to identify 1) a variant associated with XX DSD in the canine model and 2) gene expression alterations in canine embryonic gonads that could be informative to causation. Using a genome wide association study (GWAS) and whole genome sequencing (WGS), we identified a variant on C. familiaris autosome 9 (CFA9) that is significantly associated with XX DSD in the canine model and in affected purebred dogs. This is the first marker and candidate causative variant identified for inherited canine XX DSD. It lies within the canine ortholog for the human disorder (OMIM 278850), which resides on 17q24, upstream of SOX9. Gene expression studies (RNA-seq and PRO-seq) in embryonic gonads at risk of XX DSD from the canine model identified significant RSPO1 downregulation in comparison to XX controls, without significant upregulation of SOX9 or other known testis pathway genes. A novel mechanism is proposed in which the canine XX DSD variant acts upstream of RSPO1 to induce epigenomic gonadal mosaicism.

2017-10-25 | GSE92283 | GEO

RSPO1 downregulation and a CFA9 Insertion are Associated with Inherited XX DSD in a Canine Model

Project description:Remarkable progress has been achieved in understanding the mechanisms controlling sex determination, yet the cause for many Disorders of Sexual Development remains unknown. Of particular interest is a rare XX DSD subtype in which individuals are negative for SRY, the testis determining factor on the Y chromosome, yet develop testes or ovotestes, and both phenotypes occur in the same family. This is a naturally occurring disorder in humans and dogs (Canis lupus familiaris), and phenotypes in the canine XX DSD model are strikingly similar to those in this type of human XX DSD. The purposes of this study were to identify 1) a variant associated with XX DSD in the canine model and 2) gene expression alterations in canine embryonic gonads that could be informative to causation. Using a genome wide association study (GWAS) and whole genome sequencing (WGS), we identified a variant on Canis familiaris autosome 9 (CFA9) that is significantly associated with XX DSD in the canine model and in affected purebred dogs. This is the first marker and candidate mutation identified for inherited canine XX DSD, and it lies within the canine ortholog for the human disorder (OMIM 278850). Inheritance of the variant indicates that XX DSD is a complex trait in which breed genetic background affects penetrance. Furthermore, the homozygous variant genotype is associated with embryonic lethality in at least one breed. Gene expression studies (RNA-seq and PRO-seq) in embryonic gonads at risk of XX DSD from the canine model identified significant RSPO1 downregulation without significant upregulation of SOX9 or other known testis pathway genes. A novel mechanism is proposed in which the canine XX DSD mutation acts upstream of RSPO1 to induce epigenomic gonadal mosaicism.

2017-10-02 | GSE92318 | GEO

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