Rapamycin Induced Autophagy in Mesenchymal Stem Cells Modulates Cell Survival After Transplantation in a Rat Model with Cisplatin-Induced Ovarian Toxicity via Deactivation of the mTOR Pathway

Purpose: We aimed to evaluate the impact of preconditioning adipose-derived mesenchymal stem cells (ADMSCs) with the autophagy inducer rapamycin (Rapa) on Cisplatin (Cis) induced ovarian toxicity in a rat model. Methods: ADMSCs were pretreated with 50 nmol/L rapa for two h in vitro. Another in vivo study included 96 female Sprague-Dawley rats divided into four equal groups: control, Cis, Cis +ADMSCs, and Cis +ADMSCs + Rapa. Rats were sacrificed after 2 and 6 weeks. Each group was subdivided into two equal subgroups: 6 rats were sacrificed to study ovarian parameters, and six were left for mating to evaluate the fertility index. Results: Autophagy activation was detected in ADMSCs + Rapa by increasing autophagosomes, high autophagy-specific LC3-II gene and protein expression, and low expression of p62 and mTOR genes. Moreover, transplantation of ADMSCs + Rapa restored balance between E2, FSH, and LH, increased antioxidant activity, and improved follicular count and quality after 2 and 6 weeks of treatment. Fertility index analysis manifested restoring reproductive capacity in the ADMSCs+ Rapa group at both intervals. Conclusions: Autophagy induction could enhance the therapeutic capability of ADMSCs by deactivating the mTOR pathway, which in turn promotes the ovarian folliculogenesis process after exposure to Cis.