Feasibility of mesenchmyal stem cells as modulators of inflammation and as a cellular model to study cartilage damage in osteoarthritis
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Osteoarthritis (OA) is the most common degenerative condition affecting whole joints and causing pain and cartilage degeneration, particularly in the elderly population. Inflammation of the synovium is now recognised as an important clinical feature initiating and promoting disease progression. Activated macrophages and T lymphocytes infiltrating the OA synovial lining mediate inflammatory responses such as production of pro-inflammatory cytokines, which can induce destructive processes in the cartilage. In addition to this danger signals like alarmins, released as an immune response, further lead to production of soluble mediators that could accelerate cartilage matrix degradation resulting in altered chondrocyte behaviour and hypertrophy. Mesenchymal stem cells (MSCs) have been considered as an attractive option for OA cell therapy. However, inflammation induced catabolic factors are also known to negatively impact cartilage engineering strategies, perhaps inhibiting the use of therapeutic cells for the treatment of OA. The work presented in this thesis sought to investigate the use of engineered MSCs as cellular mediators of anti-inflammation via viral interleukin-10 (vIL10) expression and also the potential of an in vitro model using MSCs to study inflammation-driven cartilage damage in OA. The tetracycline system (Tet) was used to modify mouse mesenchymal stem cells (mMSCs) to over-express vIL10 via adenoviral transduction. Doxycycline acted as a pharmacological switch to control the Tet system and successfully demonstrated efficient and tightly controlled vIL10 production by mMSCs. Engineered vIL10 MSCs proved to be immunosuppressive on activated macrophages and splenocytes in vitro via juxtacrine and paracrine signalling. These finding suggest that the Tet system of inducible vIL10 expression by MSCs may serve as a feasible strategy to enhance MSC-mediated immune regulation that can be translated towards attenuation of inflammation in OA. Furthermore, a three-dimensional in vitro cartilage model to study the effects of inflammation-triggered chondrocyte alterations in OA was developed. Activation of the pathogen recognising receptor NLRP3 inflammasome pathway in the presence of the S100A8/A9 danger ligand signal, in alginate encapsulated articular chondrocyte progenitors (ACPs) and human MSCs (hMSCs) demonstrated anti-chondrogenic effects. This novel model interrogating this ligand receptor interaction could offer a new direction to control/prohibit the release of catabolic factors associated with early inflammatory responses, thereby improving MSC and/or chondroprogenitor-based cartilage engineering strategies. Overall, this thesis showcased the viability of MSCs as potential modulators of inflammation and a possible model to generate novel cartilage regeneration strategies.
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