Tissue Engineering to Improve Immature Testicular Tissue and Cell Transplantation Outcomes: One Step Closer to Fertility Restoration for Prepubertal Boys Exposed to Gonadotoxic Treatments

Abstract

Despite their important contribution to the cure of both oncological and benign diseases, gonadotoxic therapies present the risk of a severe impairment of fertility. Sperm cryopreservation is not an option to preserve prepubertal boys’ reproductive potential, as their seminiferous tubules only contain spermatogonial stem cells (as diploid precursors of spermatozoa). Cryobanking of human immature testicular tissue (ITT) prior to gonadotoxic therapies is an accepted practice. Evaluation of cryopreserved ITT using xenotransplantation in nude mice showed the survival of a limited proportion of spermatogonia and their ability to proliferate and initiate differentiation. However, complete spermatogenesis could not be achieved in the mouse model. Loss of germ cells after ITT grafting points to the need to optimize the transplantation technique. Tissue engineering, a new branch of science that aims at improving cellular environment using scaffolds and molecules administration, might be an approach for further progress. In this review, after summarizing the lessons learned from human prepubertal testicular germ cells or tissue xenotransplantation experiments, we will focus on the benefits that might be gathered using bioengineering techniques to enhance transplantation outcomes by optimizing early tissue graft revascularization, protecting cells from toxic insults linked to ischemic injury and exploring strategies to promote cellular differentiation.

Tissue-Engineered Grafts from Human Decellularized Extracellular Matrices: A Systematic Review and Future Perspectives

“…In these cases, immature testicular tissue containing spermatogonial stem cells can be cryopreserved. In adulthood, fertility could be potentially restored through transplantation of the tissue itself or its spermatogonial stem cells, or through in vitro maturation [270]. Although good results have been obtained in animals, clinical trials have not yet been performed.…”

Fertility sparing strategies for pre- and peripubertal male cancer patients

“…Autotransplantation of cryo-stored SSCs or immature testicular tissue can only be considered if there is no risk of cancer cell contamination of the testes. With regards to cell transplantation, attempts have been made to eliminate cancer cells from the testicular cell suspension through cell sorting techniques (for review see [18]) although further improvements and more powerful detection methods are required. Cell culture has also appeared useful to eliminate leukemic cells that were added to the testicular cell suspension although this study model may not be representative of cancer cell behaviour in tissues [19].…”

“…With regard to oncological patients, those with non-metastasising solid tumours could also come into consideration after tissue examination to exclude the presence of cancer cells in the tissue to be transplanted (providing that reliable techniques become available) and after fully informed patient-doctor decision and consent process. Currently, research is still ongoing to optimise tissue transplantation outcome as xenotransplantation experiments with human immature testicular tissue demonstrate a significant loss of spermatogonia, most likely due to hypoxia related to the absence of a vascular anastomosis between graft and host [18,32,33].…”

Possible use of spermatogonial stem cells in the treatment of male infertility

“…Количество ССК, которое потребуется для регенерации сперматогенеза и достижения фертильности у человека, пока еще точно не известно, но разумно предположить, что количество ССК должно быть существенно увеличено в культуре перед трансплантацией для обеспечения надежного приживления и результативного сперматогенеза. Каждая группа исследователей, сообщающая о культуре ССК человека, использовала различные методы для выделения клеток и их культивирования, различные питательные среды и матричные субстраты [51,52], различные наборы факторов роста и различные методы оценки полученных результатов. До недавнего времени ни один метод получения культур человеческих ССК не был независимо тиражирован другой исследовательской группой, и это должно произойти для подтверждения истинного успеха и достижения реального прогресса [19].…”