ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Stem Cell Res Ther. 2019 Oct 22;10(1):310. ellen.goossens@vub.be

Infertility due to spermatogonial stem cell (SSC) loss is one of the major late adverse effects related to both chemotherapy and radiotherapy, and several researchers are now focusing on the development of new techniques to preserve germ cells.

Semen sample storage is not feasible in prepubertal patients, so cryostorage of testicular tissue is considered an alternative option. Transplantation of testicular tissue or SSCs is a promising strategy to restore fertility in these patients, even if caution is needed for the risk of contamination by malignant cells in boys affected by systemic or metastatic disease. In primates, autologous transplantation of pre-pubertal testicular tissue yielded complete spermatogenesis and the live birth of a healthy monkey. New techniques transplant not only SSCs, but also the associated mesenchymal stem cells (MSCs). These cells do not trans-differentiate into germ cells, but produce paracrine factors that play a role in restoring the damaged SSC niche, thus improving the efficiency of transplantation.

This experimental study tested the safety and reproductive efficiency of TGFβ1-induced MSCs and SSCs transplant (MSi-SSCT) in a mouse model of long-term infertility, and compared fertility parameters with a control group of non-treated fertile mice. TGFβ1 was used to improve engraftment efficiency, through the reduction of inflammatory factors that cause migration of MSCs away from the testis. The overall tubular fertility index (TFI), representing the percentage of tubules containing spermatogenesis, was higher after MSi-SSCT than after SSCT alone, but the expression levels of DNA methyltransferase (DNMT) 1 and 3A in donor-derived gem cells were low, suggesting a derangement of DNA methylation pattern. The complex process of epigenetic reprogramming through DNA methylation is a crucial step during spermatogenesis. Any abnormality is likely to cause infertility, and the risk of inheriting an abnormal epigenome causing congenital defects in the offspring cannot be neglected. In this study, even if the expression levels of DNMT 1 and 3A in donor-derived gem cells were low, normal levels were restored in the offspring of transplanted mice, and no differences of DNA methylation patterns were found between healthy fertile control mice and the offspring of transplanted mice.

The results of this study are encouraging, but more extensive epigenetic analyses are needed in order to define the reproductive safety of this strategy.

Reference:

1. Fayomi AP, Peters K, Sukhwani M, Valli-Pulaski H, Shetty G, Meistrich ML, et al. Autologous grafting of cryopreserved prepubertal rhesus testis produces sperm and offspring. Reprod Biol. 2019;1319:1314–9.