When will we start transplanting prepubertal testis tissue?
(2020) 36th Annual Meeting of the ESHRE (European Society of Human Reproduction and Embryology) — Location: [Virtual Meeting] (5.July.2020)
Files
No attached file found for this publication.
Details
- Authors
- Abstract
- Testicular tissue transplantation in humans was already performed back in 1889 by Brown-Sequard to treat hypogonadism. However, grafting the tissue to restore the reproductive potential has never been reported. Efforts to preserve the fertility of prepubertal boys facing fertility-threatening therapies by cryopreserving their immature testicular tissue have motivated researchers to develop methods to give these young patients a hope to father their own genetic child. In this regard, auto-transplantation of cryostored tissue can be considered if there is no risk of cancer cell contamination of the tissue i.e. not in case of haematological cancers or metastasizing tumours. The proof of principle of the technique was recently obtained with the birth of GRADY in macaques but many research questions remain before pilot trials can be considered in humans where most often only small amounts of tissue are available for future use. Xenotransplantation experiments with human prepubertal testicular tissue in nude mice showed an important loss of spermatogonia in grafts, regardless of prior cryopreservation, justifying optimization of the avascular transplantation procedure. High DNA fragmentation by TUNEL was observed in the first days following grafting suggesting that cell damage is likely due to hypoxia before vascular supply of oxygen to the grafted tissue is in place. In this regard, finding the most appropriate graft size to reduce tissue necrosis and cell loss is a first matter of concern. Only one study compared graft outcome for different tissue sizes and no differences were observed up to 16mm³. Attempts to shorten the ischemic period before revascularization of the graft were also made by culturing the tissue fragment before grafting in media containing vascular endothelial growth factor (VEGF) as this method increased the number of seminiferous tubules with elongating spermatids in bovine. Unfortunately, this could so far not be confirmed for human prepubertal tissue although a potential benefit was suggested in a report of two cases. However, controlled local drug delivery of VEGF covering the time period needed for the stabilization of the neo-vasculature could be more efficient. Therefore, nanoparticles (NPs) containing growth factors e.g. VEGF, platelet-derived growth factor (PDGF) and necrosis inhibitors have been developed as well as tissue embedding matrices allowing proper migration of endothelial cells. Higher recovery rates of undifferentiated spermatogonia in autografts were reached in an alginate hydrogel and further improvement was achieved with NPs controlled drug delivery. Incomplete and abnormal differentiation of spermatogonia in xenografts of human prepubertal testicular tissue was also observed, most likely due the phylogenetic distance between mice and human, but not only. Indeed, graft development seems also influenced by its hormonal environment as autografting experiments in marmosets showed less advanced germ cell development in hemi-castrated than castrated animals. While it was reported that human prepubertal Leydig cells show maturation features based on the presence of key enzymes of steroidogenesis and ultrastructural modifications after xenografting, only few studies have investigated the impact of the hormonal environment on the spermatogonial stem cell niche in grafts. Some questions still need to be addressed: what would be the real impact of the post-chemotherapeutic hypergonadotropic hypogonadic state of candidate patients for autotransplantation on transplant outcome, and would hormone requirements of the transplanted tissue depend on the age of the patient at cryopreservation? Furthermore, and so far, the absence of a valid preclinical model for human prepubertal testicular tissue transplantation precludes to answer the question of the time needed to achieve complete spermatogenesis in grafts and thus the optimal moment for sperm retrieval.
- Affiliations
Citations
Wyns, C. (2020). When will we start transplanting prepubertal testis tissue? 36th Annual Meeting of the ESHRE (European Society of Human Reproduction and Embryology), [Virtual Meeting]. https://hdl.handle.net/2078.5/97692