Mesenchymal stem/stromal cells-derived extracellular vesicles as a potentially more beneficial therapeutic strategy than MSC-based treatment in a mild metabolic osteoarthritis model

Abstract

Background Mesenchymal stromal/stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) hold promise as a disease modifying treatment in osteoarthritis (OA). Obesity, and its associated inflammation, contribute to OA development and metabolic OA represents a specific and significant group of the OA patient population. Given their immunomodulatory properties, MSC and MSC-EVs are especially interesting for this group of patients as a therapeutic option. Here, we were the first to compare the therapeutic efficacy of MSCs and MSC-EVs in a mild OA model taking these metabolic aspects into consideration. Methods Male Wistar-Han rats (Crl:WI(Han) (n = 36) were fed a high fat diet for 24 weeks, with unilateral induction of OA by groove surgery after 12 weeks. Eight days after surgery rats were randomized in three treatment groups receiving MSCs, MSC-EVs or vehicle injection. Pain-associated behavior, joint degeneration, and local and systemic inflammation were measured. Results We demonstrated that despite not having a significant therapeutic effect, MSC-EV treatment results in lower cartilage degeneration, less pain behaviour, osteophytosis and joint inflammation, than MSC treatment. Suggesting that MSC-EVs could be a more promising therapeutic strategy than MSCs in this mild metabolic OA model. Conclusion In summary, we find that MSC treatment has negative effects on the joint in metabolic mild OA. This is an essential finding for the significant group of patients with metabolic OA phenotype, and might help to understand why clinical translation of MSC treatment shows varying therapeutic efficacy thus far. Our results also suggest that MSC-EV-based treatment might be a promising option for these patients, however MSC-EV therapeutic efficacy will need improvement.

Effects of different obesogenic diets on joint integrity, inflammation and intermediate monocyte levels in a rat groove model of osteoarthritis

“…The left knee joints of all animals were preserved (no surgical intervention) and served as a non-surgery control. Although it is well-documented that OA in one knee joint can lead to abnormal biomechanics in other joints in humans and dogs, and in DMM mouse models ( Mundermann et al, 2005 ; Bockstahler et al, 2009 ; Metcalfe et al, 2013 ; Fouasson-Chailloux et al, 2021 ; Alves et al, 2022 ), our relatively mild OA model with unilateral groove surgery did not show significant differences in weight bearing between the left and right joints when untreated, as shown previously ( Warmink et al, 2023 ). All surgeries were performed under general anesthesia (isoflurane–induced at 4%, maintained at 2.5%), and analgesia (0.01 mg/kg buprenorphine, injected subcutaneously prior to surgery, and 6–8 h after first injection).…”

“…We considered a difference between means of 3 points in the primary outcome (total OARSI score) clinically relevant, with a corrected α = 0.01, β = 0.2, and aiming for a power of 80%. Based on previous research the variance in grooved animals was estimated at σ 2 = 1.21 and in ungrooved animals σ 2 = 0.56 ( de Visser et al, 2017 ; de Visser et al, 2018a ; de Visser et al, 2019 ; Warmink et al, 2022 ; Warmink et al, 2023 ). This resulted in 4 animals in the grooved groups and 3 animals in the ungrooved groups, thus a total of 7 animals per diet group would be sufficient.…”

β1-Integrin-Mediated Uptake of Chondrocyte Extracellular Vesicles Regulates Chondrocyte Homeostasis

“…MSC-EVs are able to promote a greater resolving phenotype than the parent cells in a model of murine OA [13]. In fact, in a metabolically induced model of rat OA, MSC infusion further exacerbated cartilage degradation whereas MSC-EVs did not [14].…”

Adjunctive treatment of sepsis with mesenchymal stem cell-derived extracellular vesicles: a systemic review and meta-analysis of pre-clinical studies

“…Compared with cell therapy, EVs have several advantages; for example, non-immunogenicity, non-infusion toxicity, relatively higher stability in the blood circulation, easier access, uncomplicated preservation, and ethical issues (12). For clinical application, MSC-EVs attenuate patients suffering from steroid refractory graft-versus-host disease, ostheoarthitis, and grade III-IV chronic kidney disease (13)(14)(15). In sepsis, pre-clinical studies in animal models have demonstrated the bene cial e cacy of MSC-EVs in sepsis; however, the impacts of MSC-EV treatment are still inconclusive.…”