**Mesenchymal Stem/Stromal Cells-derived extracellular vesicles as a potentially more beneficial therapeutic strategy than MSC-based treatment in a mild metabolic osteoarthritis model**
Authors: Kelly Warmink (1;2), Jaqueline L. Rios (1;2), Suzy Varderidou-Minasian (1;3), Marta Torres-Torrillas (4;5), Devin R. van Valkengoed (1;2), Sabine Versteeg (6), Niels Eijkelkamp (6), Harrie Weinans (1;2;7), Nicoline M. Korthagen (1;2), Magdalena J. Lorenowicz (1;3;8)
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1 Regenerative Medicine Center, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands
2 Department of Orthopedics, University Medical Center Utrecht, 85500, 3508 GA, Utrecht, The Netherlands
3 Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands
4 Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, Valencia, Spain
5 García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU Cardenal Herrera University, CEU Universities, Valencia, Spain
6 Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 85090, 3508 AB, Utrecht, The Netherlands
7 Department of Biomechanical Engineering, Mekelweg 2, 2628 CD, TU Delft, Delft, The Netherlands
8 Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands
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**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 safer 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 safer option for these patients, however MSC-EV therapeutic efficacy will need improvement.
