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Umbilical cord mesenchymal stem cell-derived extracellular vesicles improve excessive autophagy of granulosa cells through METTL3
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DOI：10.1152/ajpcell.00785.2024.png)
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Abstract
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Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder impacting women's fertility. We assessed the effect of umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-MSC-EVs) on PTEN-induced kinase 1 (PINK1)/Parkin-mediated excessive autophagy of ovarian granulosa cells (GCs) through methyltransferase-like 3 (METTL3). Human ovarian GC line KGN was cultured and treated with dehydroepiandrosterone (DHEA) and UC-MSC-EVs. Cell apoptosis and viability, autophagy-related protein levels, adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) level, and microtubule-associated protein 1 light chain 3 beta (LC3B) and translocase of outer mitochondrial membrane 20 (TOMM20) colocalization were assessed by flow cytometry, CCK-8, Western blot, kit, and immunofluorescence. PINK1 N6-methyladenosine (m6A) modification, METTL3 levels, and PINK1 mRNA stability were determined by methylated RNA immunoprecipitation, reverse transcription quantitative polymerase chain reaction, and Western blot. The PCOS mouse model was established and treated with UC-MSC-EVs. Serum hormone and ovarian tissue autophagy-related protein levels were determined by enzyme-linked immunosorbent assay. DHEA decreased KGN cell viability and p62 level, increased PINK1, Parkin, LC3BII/I, and Beclin-1 protein levels, ATP content, MMP level, TOMM20+LC3B+ cell number, and apoptosis, which were partly abrogated by UC-MSC-EV treatment. PINK1 had m6A modification sites. METTL3 was a PINK1 m6A-modified writer protein. After DHEA treatment, KGN cells showed elevated METTL3 and PINK1 m6A modification levels and mRNA stability, whereas UC-MSC-EV treatment caused the opposite results. METTL3 overexpression partly averted UC-MSC-EVs-improved PINK1/Parkin-mediated mitophagy. UC-MSC-EVs curbed PINK1/Parkin-mediated excessive autophagy through METTL3 and improved ovarian function in PCOS mice. In conclusion, UC-MSC-EVs suppressed PINK1/Parkin-mediated mitophagy of ovarian GCs through METTL3, thereby improving PCOS.
Keywords:
extracellular vesicles
methyltransferase-like 3
ovarian granulosa cells
polycystic ovary syndrome
umbilical cord-derived mesenchymal stem cells
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