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

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

  • Pharmacol Res. 2024 Oct 19:209:107474. doi: 10.1016/j.phrs.2024.107474.
Kai Feng 1 Teng Ye 1 Xuetao Xie 1 Jiashuo Liu 1 Liangzhi Gong 1 Zhengsheng Chen 1 Juntao Zhang 1 Haiyan Li 2 Qing Li 3 Yang Wang 4
Affiliations

Affiliations

  • 1 Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
  • 2 Chemical and Environmental Engineering, School of Engineering, STEM College, RMIT University, 124 La Trobe St, Melbourne, VIC 3000, Australia.
  • 3 Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China. Electronic address: liqing_236@aliyun.com.
  • 4 Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China. Electronic address: wangyang63@sjtu.edu.cn.
Abstract

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.

Keywords

Autophagy; Chondrocyte senescence; ESC-sEVs; FOXO1A; Osteoarthritis.

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