Background: Testicular torsion is an urological emergency that may lead to infertility due to ischemic injury. Promptly surgical correction by orchiopexy is the only way to avoid infertility and no effective treatment for restoration of spermatogenesis. We previously reported that mesenchymal stem cells (MSCs), through local injection upon testicular torsion-detorsion, restored the spermatogenesis without differentiation into sperm. In this study, molecular mechanisms of MSCs in regulating germ cell activity induced by testicular torsion-detorsion were investigated. Methods: Sixteen male Sprague-Dawley rats 6-8 weeks old received left testis 720° torsion for 3 h followed by detorsion with or without MSCs. Right inguinal skin incision without testicular torsion served as control. MSCs with 3 × 104 cells were locally injected into left testis 30 min before detorsion. Three days after the surgery, orchiectomy was executed and the testis, epididymis, and sperm were separated to each other. Functional assessments on sperm included counting sperm amount and sperm motility, staining F-actin, and quantifying adenosine triphosphate (ATP) content. The hallmarks of glycogenesis and glycolysis in each tissue segment were measured by Western blot. Results: Testicular torsion-detorsion significantly decreased the amount of sperm, inhibited the motility, declined the F-actin expression, and reduced the content of ATP in sperm. Local injection of MSCs improved sperm function, particularly in sperm motility. With MSCs, ATP content and F-actin were preserved after testicular torsion-detorsion. MSCs significantly reversed the imbalance of glycolysis in sperm and testis induced by testicular torsion-detorsion, as evidenced by increasing the expression of phosphoglycerate kinase 2 and glyceraldehyde-3-phosphate dehydrogenase-spermatogenic, activating Akt, and increasing glycogen synthase kinase 3 (GSK3), which led to the increase in glycolysis cascades and ATP production. Human stem cell factor contributed the activation of Akt/GSK3 axis when sperm suffered from testicular torsion-detorsion-induced germ cell injury. Conclusions: Local injection of MSCs into a testis damaged by testicular torsion-detorsion restores sperm function mainly through the improvement of sperm motility and energy. MSCs reversed the imbalance of glycogenesis and glycolysis in sperm by regulating Akt/GSK3 axis. Thus, MSCs may potentially rescue torsion-detorsion-induced infertility via local injection.
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