Exosomes from adipose-derived stem cells alleviate premature ovarian failure via blockage of autophagy and AMPK/mTOR pathway

PeerJ. 2023 Dec 14:11:e16517. doi: 10.7717/peerj.16517. eCollection 2023.

Abstract

Objective: The objective of this study was to investigate the effects and mechanisms of adipose-derived stem cell-derived exosome (ADSCs-Exo) in treating premature ovarian failure (POF).

Methods: We constructed a POF mouse model through intraperitoneal injection of cyclophosphamide, followed by the administration of the autophagy inhibitor 3-methyladenine (3-MA). Pathological injury, follicle stimulating hormone (FSH), malondialdehyde (MDA), reactive oxygen species (ROS), estradiol (E2), superoxide dismutase (SOD), granulosa cell (GC) apoptosis, and autophagy were assessed. Exosomes isolated from ADSCs were used to treat POF in mice. The AMPK-mTOR pathway and its proteins (p-AMPK and p-mTOR) were evaluated. A POF cell model was established using cyclophosphamide-treated human ovarian granulosa-like tumor (KGN) cells. We administered ADSCs-Exo and rapamycin to validate the mechanism of ADSCs-Exo against POF.

Results: In POF mice, 3-MA treatment attenuated pathological injuries, decreased FSH, MDA, and ROS levels, and increased E2 and SOD levels. 3-MA treatment also inhibited GC apoptosis and autophagy. ADSCs-Exo alleviated pathological injuries, improved ovarian morphology and function, and reduced oxidative stress in POF mice. ADSCs-Exo inhibited GC apoptosis and autophagy. ADSCs-Exo downregulated the expression of AMPK/mTOR pathway proteins (p-AMPK and p-mTOR). In the POF cell model, ADSCs-Exo and rapamycin inhibited AMPK/mTOR-mediated autophagy.

Conclusion: ADSCs-Exo inhibits POF through the inhibition of autophagy and the AMPK/mTOR pathway. This study provides a potential target for the clinical treatment of POF.

Keywords: AMPK/mTOR pathway; Adipose-derived stem cell; Autophagy; Exosome; Premature ovarian failure.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Autophagy
  • Cyclophosphamide / adverse effects
  • Exosomes* / metabolism
  • Female
  • Follicle Stimulating Hormone / pharmacology
  • Humans
  • Menopause, Premature*
  • Mice
  • Primary Ovarian Insufficiency* / therapy
  • Reactive Oxygen Species / metabolism
  • Sirolimus / pharmacology
  • Stem Cells
  • Superoxide Dismutase / metabolism
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • AMP-Activated Protein Kinases
  • Cyclophosphamide
  • Follicle Stimulating Hormone
  • Reactive Oxygen Species
  • Sirolimus
  • Superoxide Dismutase
  • TOR Serine-Threonine Kinases

Grants and funding

This work was supported by the Inner Mongolia Autonomous Region Natural Science Fund under Grant number 2020MS08154, and the Inner Mongolia Autonomous Region Health Science and Technology Project under Grant number 202202005. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.