Abstract
Germ cell depletion in recipient testes is indispensable for successful transplantation of spermatogonial stem cells. However, we found that such treatment had an adverse effect on spermatogenesis of orthotopically transplanted donor testis tissues. In the donor tissue, the frequency of stimulated by retinoic acid (RA) 8 (STRA8) expression was reduced in germ cells, suggesting that RA signalling indispensable for spermatogenesis was attenuated in germ cell-depleted recipient testes. In this context, germ cell depletion diminished expression of testicular Aldh1a2, which is responsible for testicular RA synthesis, while Cyp26b1, which is responsible for testicular RA metabolism, was still expressed even after germ cell depletion, suggesting an alteration of the RA synthesis/metabolism ratio. These observations suggested that RA insufficiency was one of the causes of the defective donor spermatogenesis. Indeed, repetitive RA administrations significantly improved donor spermatogenesis to produce fertile offspring without any side effects. These findings may contribute to improving fertility preservation techniques for males, especially to prevent iatrogenic infertility induced by chemotherapy in prepubertal cancer patients.
Highlights
Germ cell depletion in recipient testes is indispensable for successful transplantation of spermatogonial stem cells
Testis pieces collected from mouse pups expressing enhanced green fluorescent protein (EGFP) constitutively were transplanted into the testicular interstitium of recipient testes with or without germ cell depletion induced by busulfan (Fig. 1)
It has been demonstrated that germ cell-depleted testes are more suitable hosts for SSC transplantation than healthy testes with intact germ c ells[27,28], we found that the number of G FRA1+ undifferentiated spermatogonia and the frequency of seminiferous tubules carrying M CAM+ spermatogonia were comparable between testis pieces transplanted into busulfan-treated testes and those in control recipients (Fig. 2a–d, SI Fig. S1a–d)
Summary
Germ cell depletion in recipient testes is indispensable for successful transplantation of spermatogonial stem cells. The frequency of stimulated by retinoic acid (RA) 8 (STRA8) expression was reduced in germ cells, suggesting that RA signalling indispensable for spermatogenesis was attenuated in germ cell-depleted recipient testes In this context, germ cell depletion diminished expression of testicular Aldh1a2, which is responsible for testicular RA synthesis, while Cyp26b1, which is responsible for testicular RA metabolism, was still expressed even after germ cell depletion, suggesting an alteration of the RA synthesis/ metabolism ratio. These processes require support from the germline niche consisting of Sertoli and Leydig cells in addition to the basement membrane[4,5] The former cell type was found by Enrico Sertoli as ‘nurse cells’ for germ cells, which produces GDNF and form a blood-testis barrier, both of which are indispensable for proper s permatogenesis[6]. Considering the recent strategic improvements in cancer therapy, cancer survivors suffering from male infertility will continue to increase
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