Implications of spermatogonial stem cell transplantation for the offspring Securing a healthy future

Pediatric cancer treatments have substantially improved recently, thereby increasing the patient’s life expectancy but also severe therapy-related late effects, such as infertility. A proposed therapy to restore fertility is spermatogonial stem cell autotransplantation (SSCT) starting from a cryopreserved testis biopsy. However, health assessment of SSCT-derived offspring is essential before advancing to clinical trials.
We first developed a blueprint to study the impact of future reproductive (stem cell) therapies on the health of the offspring containing a series of tests in multiple generations of mice to follow potential emerging pathologies throughout their lifetime. Subsequently, we used this blueprint to perform a blinded longitudinal preclinical study to investigate the lifelong health of two generations born after SSCT (intervention) or without SSCT (control) in a mouse model. Overall, culture and autotransplantation of SSCs into sterile males do not seem to impact the health of their offspring.
We also investigated the DNA methylation status of sperm from SSCT offspring comparing to control offspring and found overall similar between both groups. However, one differentially hypomethylated gene (Tal2) showed higher gene expression in organs of SSCT offspring that normally express this gene.
Finally, we gave an overview of the state-of-the-art to ascertain whether SSCT is sufficiently safe to proceed to clinical trials, considering recent developments from testis biopsy cryopreservation till SSCT and health of offspring. We ultimately reflect and discuss the necessity of safety studies in reproductive medicine and put the outcomes of this thesis in perspective for SSCT and other future medical assisted reproduction.