ESC-sEVs alleviate non-early-stage osteoarthritis progression by rejuvenating senescent chondrocytes via FOXO1A-autophagy axis but not inducing apoptosis

• Published in: Pharmacological research 2024-11, Vol.209, p.107474, Article 107474
• Main Authors: Feng, Kai, Ye, Teng, Xie, Xuetao, Liu, Jiashuo, Gong, Liangzhi, Chen, Zhengsheng, Zhang, Juntao, Li, Haiyan, Li, Qing, Wang, Yang
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Autophagy; Autophagy - drug effects; Cartilage, Articular - metabolism; Cartilage, Articular - pathology; Cells, Cultured; Cellular Senescence - drug effects; Chondrocyte senescence; Chondrocytes - metabolism; Chondrocytes - pathology; Disease Progression; Embryonic Stem Cells - metabolism; ESC-sEVs; Extracellular Vesicles - metabolism; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; FOXO1A; Humans; Male; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; Osteoarthritis; Osteoarthritis - metabolism; Osteoarthritis - pathology
• ISSN: 1043-6618; 1096-1186; 1096-1186
• DOI: 10.1016/j.phrs.2024.107474

Osteoarthritis (OA) is a common joint degenerative disease which currently lacks satisfactory disease-modifying treatments. Oxidative stress-mediated senescent chondrocytes accumulation is closely associated with OA progression, which abrogates cartilage metabolism homeostasis by secreting senescence-associated secretory phenotype (SASP) factors. Numerous studies suggested mesenchymal stem cells-derived small extracellular vesicles (MSC-sEVs) have been regarded as promising candidates for OA therapy. However, MSC-sEVs were applied before the occurrence of cartilage degeneration or at early-stage OA, while in clinical practice, most OA patients who present with pain are already in non-early-stage. Recently, embryonic stem cells-derived sEVs (ESC-sEVs) have been reported to possess powerful anti-aging effects. However, whether ESC-sEVs could attenuate non-early-stage OA progression remains unknown. In this study, we demonstrated ESC-sEVs ameliorated senescent phenotype and cartilage destruction in both mechanical stress-induced non-early-stage posttraumatic OA and naturally aged mice. More importantly, we found ESC-sEVs alleviated senescent phenotype by rejuvenating aged chondrocytes but not inducing apoptosis. We also provided evidence that the FOXO1A-autophagy axis played an important role in the anti-aging effects of ESC-sEVs. To promote clinical translation, we confirmed ESC-sEVs reversed senescent phenotype in ex-vivo cultured human end-stage OA cartilage explants. Collectively, our findings reveal that ESC-sEVs-based therapy is of high translational value in non-early-stage OA treatment. [Display omitted] •ESC-sEVs reversed senescent phenotype in posttraumatic OA, naturally aged mice, and cultured human OA cartilage•ESC-sEVs attenuated senescent phenotype by rejuvenating chondrocytes but not inducing apoptosis•The FOXO1A-autophagy axis played an important role in the anti-aging effects of ESC-sEVs•ESC-sEVs-based therapy is of high translational value in intervention for non-early-stage OA.