Oral Presentation ESA-SRB-AOTA 2019

Gonocyte transformation into spermatogonial stem cells (SSC): The key to understand infertility and malignancy of cryptorchidism (#250)

Ruili Li 1 2 , Amanda Vannitamby 1 , Sarah, S.K. Yue 1 , Jorien Meijer 1 , Sanduni A. Abeydeera 1 , Melissa Y. Tien 1 , Emily C. Burton 1 , Gulcan Sarila 1 , John Hutson 1 2 3
  1. F. Douglas Stephens Surgical Research Laboratory, Murdoch Children"s Research Institute, Parkville,, Victoria, Australia
  2. Department of Paediatrics, University of Melbourne, Parkville,, Victoria, Australia
  3. Urology Department, Royal Children’s Hospital, Parkville,, Victoria, Australia

Introduction

Undescended testis (UDT) is a major health problem, affecting over 2% of new-born boys with increased infertility (30-60%) and testicular cancer (5-10 fold > normal males) later in life. We have studied animal models in conjunction with human biopsies of UDT in order to understand the process of gonocyte transformation into SSC to elucidate how to prevent infertility and testicular cancer in cryptorchidism.

Methods

We used testes from Oct4-promoter-driving GFP transgenic mice, androgen receptor knockout (ARKO) mice, hypogonadal (hpg) mice, Bax knockout (BaxKO) mice and human biopsies for gene expression, immunohistochemistry and confocal imaging analysis. Serum and testes were collected for hormone analysis.

Results

We have found that mouse gonocytes transformed into SSC between postnatal days 2-6 during minipuberty when testosterone, FSH receptor and Oct4 peaked.  There was no difference for number of gonocytes transformed into SSC/tubule between ARKO mice and wild type (WT) littermates. Germ cells/tubule were significantly less in hpg mice comparing to WT. There were persisting gonocytes in BaxKO testicular tubules which were not present in WT. UDT biopsies showed empty tubules without germ cell significantly increased and number of germ cells decreased with increasing age of orchidopexy. There were persisting gonocytes in testicular tubules of congenital UDT after gonocyte transformation.

Conclusion

In conclusion, we found that gonocytes transform into SSC at 2-6 days of age in mouse. Like human minipuberty does exist in mouse and coincides with gonocyte transformation into SSC. Gonocyte transformation in mouse is independent from androgen but gonodotrophin deficiency caused germ cell death.  Disruption of apoptosis regulator, Bax, caused persisting gonocytes. Orchidopexy at older age showed significant germ cell depletion. These suggest that FSH may be important in gonocyte transformation and persisting gonocytes in congenital UDT could be due to disruption of apoptosis during gonocyte transformation, which could cause testicular cancer.