Comparison of the therapeutic effects between stem cells and exosomes in primary ovarian insufficiency

AbstractBackground:Primary ovarian insufficiency (POI) refers to the loss of ovarian function under the age of 40 and resultsin amenorrhea and infertility. Our previous studies have shown that transplantation of mesenchymal stem cells (MSCs) and MSC-derived exosomesin chemotherapy-induced POI mouse ovaries can reverse the POI and eventually achieve pregnancy. Based on our recent studies, MSC-derived exosomeshave almost equal therapeutic potentials as transplanted MSCs. However, it is still unclear whether exosomes can completely replace MSCs in POI treatment. For the reliable application of cell-free treatment for POI patients using exosomes, there is a need to understand whetherthere is any outcome and effectiveness differencebetween MSC and MSC-derived exosome treatment.Methods:Comparing the therapeutic effect of intravenous injection using MSCs and equal amountsof exosomesin aPOI mouse model will reveal the differencebetween the two therapeutic resources. In this study, we induced POI in C57/BL6 mice by chemotherapy (CXT) using a standard protocol. We then injected four different doses of MSCs or equal amountsof commercialized MSC-derived exosomesby retro-orbital injection post-CXT.Result:After MSC/exosome treatment, tissue and serum samples were harvested to analyze molecular changes after treatment,while other mice in parallel experiments underwent breeding experimentsto compare the restoration of fertility. Both the MSC- and exosome-treated groups had a restored estrous cycle and serum hormone levelscompared to untreated POI mice. The pregnancy rate in the MSC-treated group was 60% to 100% after treatment, while thepregnancy rate in the exosome-treated group was 30% to 50% after treatment. Interestingly, in terms oflong-term effects, MSC-treated mice still showed a 60% to 80% pregnancy rate in the second round of breeding, while the exosome-treated group became infertile again inthe second roundof breeding.Conclusions:Although there were some differences in the efficacy between MSC treatment and exosome treatment, both treatments were able to achieve pregnancy in the POI mouse model. In conclusion, we report that MSC-derived exosomes are apromising therapeutic option to restore ovarian function in POI conditions similar to treatment with MSCs.