Co-transplantation of mesenchymal stem cells improves spermatogonial stem cell transplantation efficiency in mice

摘要

Spermatogonial stem cell transplantation (SSCT) could become a fertility restoration tool for childhood cancer survivors. However, since in mice, the colonization efficiency of transplanted spermatogonial stem cells (SSCs) is only 12%, the efficiency of the procedure needs to be improved before clinical implementation is possible. Co-transplantation of mesenchymal stem cells (MSCs) might increase colonization efficiency of SSCs by restoring the SSC niche after gonadotoxic treatment. A mouse model for long-term infertility was developed and used to transplant SSCs (SSCT, n?=?10), MSCs (MSCT, n?=?10), a combination of SSCs and MSCs (MS-SSCT, n?=?10), or a combination of SSCs and TGF?1-treated MSCs (MSi-SSCT, n?=?10). The best model for transplantation was obtained after intraperitoneal injection of busulfan (40?mg/kg body weight) at 4?weeks followed by CdCl2 (2?mg/kg body weight) at 8?weeks of age and transplantation at 11?weeks of age. Three months after transplantation, spermatogenesis resumed with a significantly better tubular fertility index (TFI) in all transplanted groups compared to non-transplanted controls (P??0.001). TFI after MSi-SSCT (83.3?±?19.5%) was significantly higher compared to MS-SSCT (71.5?±?21.7%, P?=?0.036) but did not differ statistically compared to SSCT (78.2?±?12.5%). In contrast, TFI after MSCT (50.2?±?22.5%) was significantly lower compared to SSCT (P??0.001). Interestingly, donor-derived TFI was found to be significantly improved after MSi-SSCT (18.8?±?8.0%) compared to SSCT (1.9?±?1.1%; P??0.001), MSCT (0.0?±?0.0%; P??0.001), and MS-SSCT (3.4?±?1.9%; P??0.001). While analyses showed that both native and TGF?1-treated MSCs maintained characteristics of MSCs, the latter showed less migratory characteristics and was not detected in other organs. Co-transplanting SSCs and TGF?1-treated MSCs significantly improves the recovery of endogenous SSCs and increases the homing efficiency of transplanted SSCs. This procedure could become an efficient method to treat infertility in a clinical setup, once the safety of the technique has been proven.