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Extracellular vesicles from senescent mesenchymal stromal cells are defective and cannot prevent osteoarthritis
Jérémy Boulestreau1, Marie Maumus1, Giuliana M Bertolino1
1IRMB, University of Montpellier, INSERM U1183, Hôpital Saint-Eloi, 80 Avenue Augustin Fliche, Montpellier Cedex 5, 34295, France.
Abstract:
Age is the most important risk factor in degenerative diseases such as osteoarthritis (OA), which is associated with the accumulation of senescent cells in the joints. Here, we aimed to assess the impact of senescence on the therapeutic properties of extracellular vesicles (EVs) from human fat mesenchymal stromal cells (ASCs) in OA. We generated a model of DNA damage-induced senescence in ASCs using etoposide and characterized EVs isolated from their conditioned medium (CM). Senescent ASCs (S-ASCs) produced 3-fold more EVs (S-EVs) with a slightly bigger size and that contain 2-fold less total RNA. Coculture experiments showed that S-ASCs were as efficient as healthy ASCs (H-ASCs) in improving the phenotype of OA chondrocytes cultured in resting conditions but were defective when chondrocytes were proliferating. S-EVs were also impaired in their capacity to polarize synovial macrophages towards an anti-inflammatory phenotype. A differential protein cargo mainly related to inflammation and senescence was detected in S-EVs and H-EVs. Using the collagenase-induced OA model, we found that contrary to H-EVs, S-EVs could not protect mice from cartilage damage and joint calcifications, and were less efficient in protecting subchondral bone degradation. In addition, S-EVs induced a pro-catabolic and pro-inflammatory gene signature in the joints of mice shortly after injection, while H-EVs decreased hypertrophic, catabolic and inflammatory pathways. In conclusion, S-EVs are functionally impaired and cannot protect mice from developing OA.
Insights
Senescent fat mesenchymal stromal cells produce impaired extracellular vesicles (EVs) that fail to protect against osteoarthritis (OA) in mice. These senescent EVs (S-EVs) worsen joint damage and inflammation, unlike healthy EVs (H-EVs).
Area of Science:
- Cellular senescence
- Extracellular vesicles (EVs)
- Osteoarthritis (OA) pathogenesis
Background:
- Age is a primary risk factor for osteoarthritis (OA), linked to senescent cell accumulation in joints.
- Mesenchymal stromal cells (MSCs) and their EVs are investigated for OA therapeutics.
- The impact of cellular senescence on MSC-derived EVs for OA treatment remains unclear.
Purpose of the Study:
- To evaluate the effect of senescence in adipose-derived stem cells (ASCs) on the therapeutic potential of their extracellular vesicles (EVs) in an OA model.
- To compare the characteristics and function of EVs from healthy ASCs (H-EVs) versus senescent ASCs (S-EVs).
Main Methods:
- Induced senescence in human ASCs using etoposide.
- Isolated and characterized EVs from healthy (H-ASCs) and senescent ASCs (S-ASCs).
- Assessed EV effects on OA chondrocytes in vitro and in a collagenase-induced OA mouse model in vivo.
Main Results:
- Senescent ASCs produced more, larger EVs with less RNA; these S-EVs were less effective in improving OA chondrocyte phenotype, especially during proliferation.
- S-EVs showed impaired ability to promote anti-inflammatory macrophage polarization and contained differential protein cargo related to inflammation and senescence.
- In vivo, S-EVs failed to protect against OA progression, cartilage damage, and bone degradation, instead inducing pro-catabolic and pro-inflammatory gene expression.
Conclusions:
- Extracellular vesicles derived from senescent ASCs (S-EVs) are functionally impaired compared to those from healthy ASCs (H-EVs).
- S-EVs do not offer therapeutic benefits in OA models and may exacerbate disease progression.
- Cellular senescence negatively impacts the therapeutic efficacy of ASC-derived EVs for osteoarthritis.
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