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Cytokine‐induced interleukin‐1 receptor antagonist protein expression in genetically engineered equine mesenchymal stem cells for osteoarthritis treatment
| Content Provider | Semantic Scholar |
|---|---|
| Author | Gabner, Simone Ertl, Reinhard Velde, Karsten Renner, Matthias Jenner, Florien Egerbacher, Monika Hlavaty, Juraj |
| Copyright Year | 2018 |
| Abstract | BACKGROUND A combination of tissue engineering methods employing mesenchymal stem cells (MSCs) together with gene transfer takes advantage of innovative strategies and highlights a new approach for targeting osteoarthritis (OA) and other cartilage defects. Furthermore, the development of systems allowing tunable transgene expression as regulated by natural disease-induced substances is highly desirable. METHODS Bone marrow-derived equine MSCs were transduced with a lentiviral vector expressing interleukin-1 receptor antagonist (IL-1Ra) gene under the control of an inducible nuclear factor-kappa B-responsive promoter and IL-1Ra production upon pro-inflammatory cytokine stimulation [tumor necrosis factor (TNF)α, interleukin (IL)-1β] was analysed. To assess the biological activity of the IL-1Ra protein that was produced and the therapeutic effect of IL-1Ra-expressing MSCs (MSC/IL-1Ra), cytokine-based two- and three-dimensional in vitro models of osteoarthritis using equine chondrocytes were established and quantitative real-time polymerase chain reaction (PCR) analysis was used to measure the gene expression of aggrecan, collagen IIA1, interleukin-1β, interleukin-6, interleukin-8, matrix metalloproteinase-1 and matrix metalloproteinase-13. RESULTS A dose-dependent increase in IL-1Ra expression was found in MSC/IL-1Ra cells upon TNFα administration, whereas stimulation using IL-1β did not lead to IL-1Ra production above the basal level observed in nonstimulated cells as a result of the existing feedback loop. Repeated cycles of induction allowed on/off modulation of transgene expression. In vitro analyses revealed that IL-1Ra protein present in the conditioned medium from MSC/IL-1Ra cells blocks OA onset in cytokine-treated equine chondrocytes and co-cultivation of MSC/IL-1Ra cells with osteoarthritic spheroids alleviates the severity of the osteoarthritic changes. CONCLUSIONS Thus, pro-inflammatory cytokine induced IL-1Ra protein expression from genetically modified MSCs might represent a promising strategy for osteoarthritis treatment. |
| Starting Page | 15 |
| Ending Page | 27 |
| Page Count | 13 |
| File Format | PDF HTM / HTML |
| PubMed reference number | 29608232v1 |
| Alternate Webpage(s) | https://doi.org/10.1002/jgm.3021 |
| DOI | 10.1002/jgm.3021 |
| Journal | The journal of gene medicine |
| Volume Number | 20 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Bone Marrow Cartilage Chondrocyte Culture Media, Conditioned Degenerative polyarthritis Dose-dependent Gene Expression Gene Transfer Genetic Engineering Herpesvirus 1, Equid Interleukin 1 Receptor Antagonist Protein Interleukins Matrix Metalloproteinase 13 Matrix Metalloproteinases, Membrane-Associated Mesenchymal Stem Cells Polymerase Chain Reaction TNF gene Tissue Engineering Transgenes cellular targeting cytokine protein expression tumor necrosis |
| Content Type | Text |
| Resource Type | Article |
