Immunomodulation by interleukin-10 overexpressing mesenchymal stem cells for cartilage repair in osteoarthritis
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Although osteoarthritis (OA) is typically characterised by the loss or damage to articular cartilage, inflammation of the synovial membrane is now recognised as a prevalent feature believed to contribute to both symptoms and disease progression. Macrophages localised to the synovial lining are primary mediators of inflammation in the joint, responsible for the production of pro-inflammatory cytokines which can induce destructive processes in neighbouring cartilage. Furthermore, T lymphocytes have been identified as the most abundant infiltrating immune cells present in OA synovium. The release of pro-inflammatory cytokines as well as soluble mediators produced by inflamed synovium may accelerate cartilage matrix degradation. Furthermore, osteoarthritic synovium may inhibit the chondrogenic differentiation of Mesenchymal Stem Cells (MSCs) in cell replacement strategies for the treatment of OA. In light of the increasing evidence highlighting the role of inflammation in driving OA progression, this thesis sought to investigate the use of MSCs as a gene therapy vehicle to deliver anti-inflammatory vIL-10 for treatment of OA. This thesis has demonstrated that human MSCs are a suitable vehicle to achieve constitutive vIL-10 overexpression, which has immunomodulatory activity on activated immune cells in vitro, as well as naive and activated T cells in vivo during collagenase¿induced OA in mice. These findings suggest that vIL-10 overexpression by MSCs may serve as a useful strategy to maximise the immunomodulatory potential of MSCs for the treatment of OA. Furthermore, in a cohort of OA patients that has an inflammatory component associated with disease pathogenesis, administration of vIL-10 overexpressing MSCs may modulate inflammatory processes and alter disease progression. Additionally, this thesis has identified M1-polarised macrophages as mediators of the inhibitory effect of OA synovium on MSC chondrogenesis. This data highlights M1-polarised synovial macrophages as a potential therapeutic target to improve the efficacy of current MSC-based cartilage repair strategies for the treatment of OA.
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