Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of Which Leads to Masculinization Disorders in Rodents

Driesche, Sander van den; Walker, Marion; McKinnell, Chris; Scott, Hayley M.; Eddie, Sharon L.; Mitchell, Rod T; Seckl, Jonathan R.; Drake, Amanda J.; Smith, Lee B.; Anderson, Richard A.; Sharpe, Richard M.

doi:10.1371/journal.pone.0037064

Cited by 79 publications

(96 citation statements)

References 50 publications

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“…Our data show that, in fetal life, these stem cells increase >17-fold in number from e15.5 to e21.5 in rats when intratesticular testosterone levels are high/increasing (33,40).…”

Section: Discussionmentioning

confidence: 62%

“…1). However, there are other cell types present in or bordering the interstitium, such as macrophages, pericytes, endothelial cells, and peritubular myoid cells, which are alternative sources of regenerating adult Leydig cells, although of these cell types, only the peritubular myoid cells express COUP-TFII (33).…”

Section: Resultsmentioning

confidence: 99%

“…Although these findings suggest that androgen action on adult Leydig stem cells is important for their normal development, Ar is deleted in other cell types, and all testes are cryptorchid in ArKOs, which are confounding factors. Therefore, we used a rat model in which intratesticular testosterone in the fetus was experimentally reduced (33) and investigated if similar effects on adult Leydig cell/stem cell development occurred, which was evident in ArKOs.…”

Section: Resultsmentioning

confidence: 99%

“…We show that this differentiation pattern recapitulates what happens during normal puberty in the rat. GATA4 is important for differentiation of fetal Leydig cells (34), which also derive from COUP-TFII-expressing interstitial cells (33). GATA4 may also be imperative for development of adult Leydig cells (52), because it induces expression of steroidogenic factor-1 and StAR (53).…”

Section: Discussionmentioning

confidence: 99%

“…In adults, blood was collected by cardiac puncture into a heparinized syringe. Testes were dissected, weighed, and either frozen for RNA analysis or fixed in Bouins (6 h) before processing into paraffin wax (33). Sections (5 μm) were mounted on charged microscope slides (VWR) and dried overnight at 50°C.…”

Section: -Hsd3mentioning

confidence: 99%

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Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Kilcoyne

Smith

Atanassova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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160

135

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Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk.adult Leydig stem/progenitor cells | compensated Leydig cell failure | GATA4 | ethane dimethane sulfonate

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“…Our data show that, in fetal life, these stem cells increase >17-fold in number from e15.5 to e21.5 in rats when intratesticular testosterone levels are high/increasing (33,40).…”

Section: Discussionmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: -Hsd3mentioning

confidence: 99%

See 3 more Smart Citations

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Kilcoyne

Smith

Atanassova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

160

135

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Differentiation of Peritubular Myoid‐Like Cells from Human Induced Pluripotent Stem Cells

Robinson¹,

Haegert²,

Li³

et al. 2023

Advanced Biology

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treatments is hampered due to our limited understanding of the underlying function of normal human testicular cell-typespecific function, as well as cell-type-specific dysfunction contributing to spermatogenic failure. The somatic cells contributing to the spermatogenic niche include Sertoli cells, peritubular myoid cells (PTMs), Leydig cells, macrophages, and endothelial cells. PTMs, in combination with Sertoli cells, constitute a barrier surrounding the seminiferous tubules. A frequent finding in the cellular histology of infertile males is defects in the architecture of this barrier, suggesting a dysregulation in its formation or regulation, [2] and consequently the local spermatogenic microenvironment. [3] PTMs occupy the boundary separating the interstitial Leydig cell compartment from the germ cell tubular compartment, and contribute an important element to seminiferous tubule cytoarchitecture and cell regulation within the somatic niche (Figure 1). PTMs remain poorly characterized despite their importance. Our understanding of PTMs is derived predominately from rodent cell cultures and knock-out mouse models. These in vitro and in vivo studies have shown that PTMs are responsive to androgen stimulation, as evidenced by increased secretion Infertility affects 10-15% of couples, with half attributed to male factors. An improved understanding of the cell-type-specific dysfunction contributing to male infertility is needed to improve available therapies; however, human testicular tissues are difficult to obtain for research purposes. To overcome this, researchers have begun to use human induced pluripotent stem cells (hiPSCs) to generate various testis-specific cell types in vitro. Peritubular myoid cells (PTMs) are one such testicular cell type that serves a critical role in the human testis niche but, to date, have not been derived from hiPSCs. This study set forth to generate a molecular-based differentiation method for deriving PTMs from hiPSCs, mirroring in vivo patterning factors. Whole transcriptome profiling and quantitative polymerase chain reaction (qPCR) show that this differentiation method is sufficient to derive cells with PTM-like transcriptomes, including upregulation of hallmark PTM functional genes, secreted growth and matrix factors, smooth muscle, integrins, receptors, and antioxidants. Hierarchical clustering shows that they acquire transcriptomes similar to primary isolated PTMs, and immunostaining shows the acquisition of a smooth muscle phenotype. Overall, these hiPSC-PTMs will allow in vitro study of patient-specific PTM development and function in spermatogenesis and infertility.

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Xenotransplantation Models to Study the Effects of Toxicants on Human Fetal Tissues

Spade

McDonnell

Heger

et al. 2014

Birth Defects Research Pt B

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Many diseases that manifest throughout the lifetime are influenced by factors affecting fetal development. Fetal exposure to xenobiotics, in particular, may influence the development of adult diseases. Established animal models provide systems for characterizing both developmental biology and developmental toxicology. However, animal model systems do not allow researchers to assess the mechanistic effects of toxicants on developing human tissue. Human fetal tissue xenotransplantation models have recently been implemented to provide human-relevant mechanistic data on the many tissue-level functions that may be affected by fetal exposure to toxicants. This review describes the development of human fetal tissue xenotransplant models for testis, prostate, lung, liver, and adipose tissue, aimed at studying the effects of xenobiotics on tissue development, including implications for testicular dysgenesis, prostate disease, lung disease, and metabolic syndrome. The mechanistic data obtained from these models can complement data from epidemiology, traditional animal models, and in vitro studies to quantify the risks of toxicant exposures during human development.

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Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of Which Leads to Masculinization Disorders in Rodents

Cited by 79 publications

References 50 publications

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Differentiation of Peritubular Myoid‐Like Cells from Human Induced Pluripotent Stem Cells

Xenotransplantation Models to Study the Effects of Toxicants on Human Fetal Tissues

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