Research Paper Volume 16, Issue 21 pp 13252—13270
Anti-aging effect of extracellular vesicles from mesenchymal stromal cells on senescence-induced chondrocytes in osteoarthritis
- 1 IRMB, University of Montpellier, INSERM, Montpellier, France
- 2 Department of Rheumatology, Clinical Immunology and Osteoarticular Disease Therapeutic Unit, CHU de Montpellier, Montpellier, France
Received: February 10, 2024 Accepted: November 15, 2024 Published: November 22, 2024
https://doi.org/10.18632/aging.206158How to Cite
Copyright: © 2024 Boulestreau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Age is the most important risk factor for degenerative diseases such as osteoarthritis (OA). It is associated with the accumulation of senescent cells in joint tissues that contribute to the pathogenesis of OA, in particular through the release of senescence-associated secretory phenotype (SASP) factors. Mesenchymal stromal cells (MSCs) and their derived extracellular vesicles (EVs) are promising treatments for OA. However, the senoprotective effects of MSC-derived EVs in OA have been poorly investigated. Here, we used EVs from human adipose tissue-derived MSCs (ASC-EVs) in two models of inflammaging (IL1β)- and DNA damage (etoposide)-induced senescence in OA chondrocytes. We showed that the addition of ASC-EVs was effective in reducing senescence parameters, including the number of SA-β-Gal-positive cells, the accumulation of γH2AX foci in nuclei and the secretion of SASP factors. In addition, ASC-EVs demonstrated therapeutic efficacy when injected into a murine model of OA. Several markers of senescence, inflammation and oxidative stress were decreased shortly after injection likely explaining the therapeutic efficacy. In conclusion, ASC-EVs exert a senoprotective function both in vitro, in two models of induced senescence in OA chondrocytes and, in vivo, in the murine model of collagenase-induced OA.
Abbreviations
ACAN: aggrecan; ADAMTS: a disintegrin and metalloproteinase with thrombospondin motive; ASC: adipose-derived mesenchymal stromal cells; CDKI: cyclin-dependent kinase inhibitor; CIOA: collagenase-induced osteoarthritis; COL: collagen; CT: control; CTCF: corrected total cell fluorescence; DDR: DNA damage response; ETO: etoposide; EV: extracellular vesicle; FCS: fetal calf serum; γH2AX: phosphorylated form of histone H2AX; Glu: glutamine; HD: high dose; HGF: hepatocyte growth factor; IL: interleukin; LD: low dose; MD: medium dose; MSC: mesenchymal stromal cell; MMP: matrix metalloproteinase; NT: non-treated; OA: osteoarthritis; PS: penicillin/streptomycin; RPS9: ribosomal protein S9; RT-qPCR: reverse transcriptase-quantitative polymerase chain reaction; SA-βGAL: senescence associated-β Galactosidase; SASP: senescence associated secretory phenotype; SOX9: sex determining region Y-box 9; VEGF: vascular endothelial growth factor.