Xenografting of human fetal testis tissue: a new approach to study fetal testis development and germ cell differentiation

Mitchell, Rod T; Saunders, Philippa T. K.; Childs, Andrew J.; Cassidy-Kojima, C; Anderson, Richard A.; Wallace, W. Hamish B.; Kelnar, C. J. H.; Sharpe, Richard M.

doi:10.1093/humrep/deq183

Cited by 76 publications

(88 citation statements)

References 36 publications

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“…Second trimester (14-18 wk) human fetal testes were obtained after termination of pregnancy. Women gave consent in accordance with United Kingdom national guidelines (70), and ethical approval was obtained from the local research ethics committee (71). Marmoset fetal testes (72) and mouse fetal testes (e18.5) (33) were obtained as described earlier.…”

Section: -Hsd3mentioning

confidence: 99%

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.

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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Section: -Hsd3mentioning

confidence: 99%

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.

160

135

View full text Add to dashboard Cite

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“…Testes were isolated from pnd8 mice, fragmented and digested to obtain a single-cell suspension, and injected (5-6 grafts per animal) subcutaneously into the back of castrated male CD1 nude mice as previously described (Mitchell et al, 2010). Grafts of Matrigel (BD Biosciences) suspended isolated cells were retrieved 28 d later, weighed and fixed in Bouin's solution for 2 hours.…”

Section: Testis Dissociation and Xenograftingmentioning

confidence: 99%

Sertoli cells control peritubular myoid cell fate and support adult Leydig cell development in the prepubertal testis

et al. 2014

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Sertoli cells (SCs) regulate testicular fate in the differentiating gonad and are the main regulators of spermatogenesis in the adult testis; however, their role during the intervening period of testis development, in particular during adult Leydig cell (ALC) differentiation and function, remains largely unknown. To examine SC function during fetal and prepubertal development we generated two transgenic mouse models that permit controlled, cell-specific ablation of SCs in pre-and postnatal life. Results show that SCs are required: (1) to maintain the differentiated phenotype of peritubular myoid cells (PTMCs) in prepubertal life; (2) to maintain the ALC progenitor population in the postnatal testis; and (3) for development of normal ALC numbers. Furthermore, our data show that fetal LCs function independently from SC, germ cell or PTMC support in the prepubertal testis. Together, these findings reveal that SCs remain essential regulators of testis development long after the period of sex determination. These findings have significant implications for our understanding of male reproductive disorders and wider androgen-related conditions affecting male health.

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“…The subcutaneous transplantation of pieces of testis tissue in immunodeficient hosts allows complete spermatogenesis in fresh and cryopreserved neonatal and pre-pubertal testicular tissue from different species including rhesus macaque and human into mouse host (65). Xenografts are useful models to study spermatogenesis, toxicological effects, influence of irradiation and the cryopreservation of testicular tissues (66). This technique may be modified to study genes involved in SD and testis development in vitro.…”

Section: Establishing Causalitymentioning

confidence: 99%

Anomalies in human sex determination provide unique insights into the complex genetic interactions of early gonad development

et al. 2017

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Human sex determination (SD) involves complex mutually antagonistic genetic interactions of testis‐ and ovary‐determining pathways. For many years, both male and female SD were considered to be regulated by a linear cascade of pro‐male and pro‐female genes, respectively; however, it has become clear that male and female development is achieved through the repression of the alternative state. A gene determining the formation of a testis may function by repressing the female state and vice versa. Uniquely in development, SD is achieved by suppression of the alternate fate and maintained in adulthood by a mutually antagonistic double‐repressive pathway. Here, we review genetic data generated through large‐scale sequencing approaches that are changing our view of how this system works, including the recently described recurrent NR5A1 p.R92W mutation associated with testis development in 46,XX children. We also review some of the unique challenges in the field to establish that mutations, such as this are pathogenic. The impending surge of new genetic data on human SD from sequencing projects will create opportunities for the development of mechanistic models that will clarify how the system operates and importantly provide data to understand how selection and developmental processes interact to direct the evolution of SD across species.

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Xenografting of human fetal testis tissue: a new approach to study fetal testis development and germ cell differentiation

Cited by 76 publications

References 36 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

Sertoli cells control peritubular myoid cell fate and support adult Leydig cell development in the prepubertal testis

Anomalies in human sex determination provide unique insights into the complex genetic interactions of early gonad development

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