Bone marrow mesenchymal stem cell-derived exosomal miR-144-5p improves rat ovarian function after chemotherapy-induced ovarian failure by targeting PTEN

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Abstract

Chemotherapy-induced premature ovarian failure (POF) in women is currently clinically irreversible. Bone marrow mesenchymal stem cells (BMSCs) are a promising cellular therapeutic strategy for POF. However, the underlying mechanism governing the efficacy of BMSCs in treating POF has not been determined. In this study, we show that BMSC and BMSC-derived exosome transplantation can significantly recover the estrus cycle, increase the number of basal and sinus follicles in POF rats, increase estradiol (E2) and anti-Mullerian hormone (AMH) levels, and reduce follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels in the serum. Furthermore, we demonstrate that BMSC-derived exosomes prevent ovarian follicular atresia in cyclophosphamide (CTX)-treated rats via the delivery of miR-144-5p, which can be transferred to cocultured CTX-damaged granulosa cells (GCs) to decrease GC apoptosis. A functional assay revealed that overexpression of miR-144-5p in BMSCs showed efficacy against CTX-induced POF, and the improvement in the repair was related to the inhibition of GC apoptosis by targeting PTEN. The opposite effect was exhibited when miR-144-5p was inhibited. Taken together, our experimental results provide new information regarding the potential of using exosomal miR-144-5p to treat ovarian failure.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (grant nos. 81402165/81672913/81871343), the Social Development Project of Jiangsu (grant no. BE2018693/BE2017698), the Natural Science Foundation of Jiangsu Province (BK20171311/BK20181226), the Six Talent Peaks Project in Jiangsu Province (grant no. 2016-WSW-125), the “333 Project” Research Projects of Jiangsu Province (BRA2016141), the Jiangsu Provincial Medical Youth Talent (QNRC2016460, FRC201788), and the Scientific Research Project of Maternal and Child Health of Jiangsu Province (F201865).

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Correspondence to Wenlin Xu or Yuefeng Li or Xiaolan Zhu.

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