The Fate of Spermatogonial Stem Cells in the Cryptorchid Testes of RXFP2 Deficient Mice

Lydia Ferguson,Alexander I Agoulnik,Javier J How,Wei Yan

doi:10.1371/journal.pone.0077351

Lydia Ferguson, Alexander I Agoulnik + Show 2 more

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https://doi.org/10.1371/journal.pone.0077351

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Abstract

The environmental niche of the spermatogonial stem cell pool is critical to ensure the continued generation of the germ cell population. To study the consequences of an aberrant testicular environment in cryptorchidism we used a mouse model with a deletion of Rxfp2 gene resulting in a high intra-abdominal testicular position. Mutant males were infertile with the gross morphology of the cryptorchid testis progressively deteriorating with age. Few spermatogonia were identifiable in 12 month old cryptorchid testes. Gene expression analysis showed no difference between mutant and control testes at postnatal day 10. In three month old males a decrease in expression of spermatogonial stem cell (SSC) markers Id4, Nanos2, and Ret was shown. The direct counting of ID4+ cells supported a significant decrease of SSCs. In contrast, the expression of Plzf, a marker for undifferentiated and differentiating spermatogonia was not reduced, and the number of PLZF+ cells in the cryptorchid testis was higher in three month old testes, but equal to control in six month old mutants. The PLZF+ cells did not show a higher rate of apoptosis in cryptorchid testis. The expression of the Sertoli cell FGF2 gene required for SSC maintenance was significantly reduced in mutant testis. Based on these findings we propose that the deregulation of somatic and germ cell genes in the cryptorchid testis, directs the SSCs towards the differentiation pathway. This leads to a depletion of the SSC pool and an increase in the number of PLZF+ spermatogonial cells, which too, eventually decreases with the exhaustion of the stem cell pool. Such a dynamic suggests that an early correction of cryptorchidism is critical for the retention of the SSC pool.

Highlights

IntroductionCryptorchidism (undescended testes) is the most common congenital abnormality and affects around 2-4% of newborn boys worldwide
Cryptorchidism is the most common congenital abnormality and affects around 2-4% of newborn boys worldwide
We demonstrated a reduction in somatic cell growth factor Fgf2 gene expression in the cryptorchid testis that may alter the balance of spermatogonial stem cell (SSC) self-renewal and differentiation

Summary

Introduction

Cryptorchidism (undescended testes) is the most common congenital abnormality and affects around 2-4% of newborn boys worldwide. The degree of abnormalities strongly correlates with the testicular position of non-scrotal gonads, with testes located in a high intra-abdominal position most affected. It is generally accepted that the high temperature environment of an intra-abdominal testicular position inhibits the correct maturation and differentiation of germ cells. The most sensitive cells are primary spermatocytes and round spermatids which show early DNA damage after heat stress [4,5,6], while the spermatogonia and elongated spermatids are more resistant to high temperatures [7]. Many cell signaling pathways critical for spermatogenesis are vulnerable to heat stress and their disruption has been linked to spermatogenic arrest in the cryptorchid testis. The aberrant testicular environment has been shown to have a detrimental effect on testicular somatic cells such as Sertoli and Leydig cell function, that may lead to an inability to support germ cell maintenance and differentiation [1,4]

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