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

Lab Invest. 2020 Mar;100(3):342-352. doi: 10.1038/s41374-019-0321-y. Epub 2019 Sep 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects*
  • Cyclophosphamide / adverse effects
  • Disease Models, Animal
  • Exosomes / chemistry
  • Exosomes / metabolism
  • Female
  • Mesenchymal Stem Cells / chemistry
  • Mesenchymal Stem Cells / metabolism*
  • MicroRNAs* / metabolism
  • MicroRNAs* / pharmacology
  • Ovary / drug effects*
  • Ovary / physiology
  • Ovary / physiopathology
  • PTEN Phosphohydrolase / metabolism*
  • Primary Ovarian Insufficiency / chemically induced
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • MIRN144 microRNA, rat
  • MicroRNAs
  • Cyclophosphamide
  • PTEN Phosphohydrolase
  • Pten protein, rat