Spermidine induces cytoprotective autophagy of female germline stem cells in vitro and ameliorates aging caused by oxidative stress through upregulated sequestosome-1/p62 expression

• Published in: Cell & bioscience Vol. 11; no. 1; pp. 1 - 107
• Main Authors: Yuan, Xiaoyan, Tian, Geng. G, Pei, Xiuying, Hu, Xiaopeng, Wu, Ji
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 07.06.2021; BioMed Central; BMC
• Subjects: 1-Phosphatidylinositol 3-kinase; Age; Aging; AKT protein; Analysis; Anti- oxidative stress; Anti-aging; Apoptosis; Autophagy; Bioinformatics; Enzyme inhibitors; Female germline stem cells; Fertility; Genetic research; Germ cells; Homeostasis; Hydrogen peroxide; Microtubule-associated protein 1; Oogenesis; Ovaries; Oxidative stress; p16 Protein; p53 Protein; p62; Phagocytosis; Phosphorylation; Polyamines; Protein expression; Proteins; RNA sequencing; Senescence; Spermidine; Stem cells; TOR protein; Tumor proteins; China
• ISSN: 2045-3701; 2045-3701
• DOI: 10.1186/s13578-021-00614-4

Autophagy is required for oogenesis and plays a critical role in response to aging caused by oxidative stress. However, there have been no reports on regulation of cytoprotective autophagy in female germline stem cells (FGSCs) in response to aging caused by oxidative stress. We found that Spermidine (SPD) significantly increased protein expression of autophagy markers microtubule-associated protein 1 light chain 3 beta-II (MAP1LC3B-II/LC3B-II) and sequestosome-1/p62 (SQSTM1/p62), and evoked autophagic flux in FGSCs. Moreover, SPD increased the number and viability of FGSCs in vitro. Further, we found that SPD significantly reduced basal or hydrogen peroxide (H.sub.2O.sub.2)-induced up-regulated protein expression of the aging markers, cyclin dependent kinase inhibitor 2A (p16/CDKN2A) and tumor protein 53 (p53). After knockdown of p62 in FGSCs, p16 protein levels were significant higher compared with controls. However, protein p16 levels were not significantly changed in p62 knockdown FGSCs with SPD treatment compared with without SPD. Moreover, SPD significantly changed the expression of autophagy-related genes and pathways in FGSCs, as shown by bioinformatics analysis of RNA sequencing data. Additionally, SPD significantly inhibited AKT/mTOR phosphorylation. SPD induces cytoprotective autophagy in FGSCs in vitro and ameliorates cellular senescence of FGSCs induced by H.sub.2O.sub.2. Furthermore, SPD can ameliorate cellular senescence of FGSCs through p62. SPD might induce autophagy in FGSCs via the PI3K/Akt pathway. Our findings could be helpful for delaying aging of female germ cells due to oxidative stress and preserving female fertility.