Adipose-derived stem cells exosomal KLF3-AS1 attenuates ovarian function by YBX1/PI3K/Akt/mTOR signaling

Zhao, Wei and Zhang, Haili and Zhang, Liyan and Hai, Caizhu and Liu, Shujun and Li, Haiyan and Zhang, Yanan and Wang, Hongwu and Wang, Caisheng (2025) Adipose-derived stem cells exosomal KLF3-AS1 attenuates ovarian function by YBX1/PI3K/Akt/mTOR signaling. PHYSIOLOGY INTERNATIONAL, 112 (2). pp. 171-186. ISSN 2498-602X

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Abstract

Background: Adipose-derived stem cell (ADSC) derived exosomes have been widely studied in disease treatment. Exosomes are able to deliver bioactive molecules, including non-coding RNAs and proteins. Long non-coding RNAs (lncRNAs) are non-coding RNAs longer than 200 nucleotides and are enriched in exosomes. This work aimed to explore the effects of lncRNA KLF3 antisense RNA 1 (KLF3-AS1) that delivered by ADSC-derived exosomes on ovarian aging. Methods: ADSCs were isolated and characterized with the surface biomarkers. Exosomes were isolated from ADSCs. The biomarkers of ADSC-derived exosomes were identified using western blotting. Exosomes were labeled with PKH26 and internalized by primary granulosa cells (pGCs), and relative images were taken under fluorescence microscope. ADSCs were transfected with KLF3-AS1, and exosomes were isolated for treatment of aging female mice. The ovary weight was recorded. The follicular development was measured by Hematoxylin and eosin (H&E) staining and Masson’s trichrome staining. Apoptosis of ovary tissues was detected by TUNEL assay. The senescence and apoptosis of pGCs were determined by S-β-gal staining kit and Annexin V/PI detection kit. RNA pulldown and RNA Immunoprecipitation Chip (RIP) assay were performed to determine the interaction of Y box binding protein 1 (YBX1) with KLF3-AS1. Results: The ADSC-derived exosomes could deliver KLF3- AS1 to pGCs. Treatment with ADSC-derived exosomes notably elevated the ovary weight and enhanced follicular development in aged mice, whereas depletion of KLF3-AS1 reversed these effects and promoted cell apoptosis. ADSCs-derived exosomes alleviated senescence and apoptosis of pGCs, while KLF3-AS1 depletion blocked these phenotypes. KLF3-AS1 directly interacts with YBX1. KLF3-AS1 depletion inhibited phosphorylation of PI3K, Akt, and mTOR in pGC, and overexpression of YBX1 reversed these phenotypes. Conclusion: ADSC-derived exosomal KLF3-AS1 could improve ovary aging and enhance pGC viability via targeting the YBX1 and PI3K/AKT/mTOR signaling.

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