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

Abstract

BackgroundSpermatogonial 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.MethodsA 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 TGFß1-treated MSCs (MSi-SSCT, n = 10).ResultsThe 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 TGFß1-treated MSCs maintained characteristics of MSCs, the latter showed less migratory characteristics and was not detected in other organs.ConclusionCo-transplanting SSCs and TGFß1-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.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1065-0) contains supplementary material, which is available to authorized users.

Does co-transplantation of mesenchymal and spermatogonial stem cells improve reproductive efficiency and safety in mice?

“…RFP + MSC-derived pups were not observed. Indeed, also in our previous study, RFP + MSC-derived spermatogenesis could not be observed, although few MSCs coexpressed the germ cell marker MVH [21].…”

“…It would have been interesting to evaluate the transplantation of TGFβ-treated MSCs alone. In our previous study [21], we included the transplantation of nontreated MSCs and showed that MSCs could help to restore endogenous spermatogenesis. Also, in the group transplanted with both SSCs and TGFβ-treated MSCs, endogenous spermatogenesis recovered.…”

“…Recently, we showed that transforming growth factor beta 1 (TGFβ1)induced MSCs improved SSCT efficiency in an infertile mouse model. Although the overall tubular fertility index (TFI) was similar, after co-transplanting TGFβ1induced MSCs and SSCs (MSi-SSCT), the donor-derived TFI was ten times higher compared to that after SSCT [21]. However, the reproductive efficiency and safety were not evaluated.…”

Restoration of functional sperm production in irradiated pubertal rhesus monkeys by spermatogonial stem cell transplantation

“…Recent evidence has shown that transplantation of mesenchymal or endothelial cells into the testis interstitium or tubules, either before or 5 weeks after busulfan injection, can enhance the subsequent recovery of spermatogenesis from surviving endogenous stem cells 37‐40 . In the current study, a mixture of rhesus monkey testicular cells were injected into the irradiated testes, and it is likely that there are mesenchymal and endothelial cells present in the suspension, which might stimulate recovery of spermatogenesis from surviving endogenous SSCs.…”

<p>Role of stem cells in fertility preservation: current insights</p>

“…This observation could be explained by the lower expression of genes involved in inflammation and cell migration in TGFβ1-treated MSCs, resulting in reduced lymphatic migration toward other organs. 140 SCs to restore fertility in the female…”