The assessment of the therapeutic potential of induced pluripotent stem cell-derived mesenchymal stromal cells
Creaven, Dale
Creaven, Dale
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Publication Date
2024-11-08
Type
doctoral thesis
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Abstract
Osteoarthritis (OA) is a chronic disease that affects synovial joints. OA progression leads to loss of articular cartilage and inflammation. OA is the leading cause of adult disability worldwide. Currently, there are limited regenerative treatments for OA, and the modern standard of care focuses on reducing pain and improving mobility. Mesenchymal stromal cells (MSC) are the most widely studied cell in the cell therapy field. In vitro and in vivo data suggest that MSC are a promising treatment for several disorders, including OA. MSC mediate disease progression by modulating the immune system via cell-to-cell contact, secreted factors, and apoptosis. Although pre-clinical studies show MSC to be a promising candidate for cell therapy, progression to the clinic has failed to meet the pre-clinical hype. The heterogeneity of MSC from different sources and donors is a plausible rationale for MSC failing to gain widespread regulatory approval. Secondly, many clinical trials report minimal efficacy of MSC treatment groups compared to placebo. Induced pluripotent stem cell (ISPC) technologies have revolutionised the field of cell therapies and offer an alternative method for cell production. iPSC-MSC or iMSC might offer an alternative source of MSC with improved expandability and reduced heterogeneity. Subsequently, licensing or the in vitro priming of MSC was shown to be a viable method to attempt to improve MSC therapeutic capacity. iMSC and MSC were compared for their ability to undergo tri-lineage differentiation, secrete antiinflammatory factors and modulate the activation of immune cells, T lymphocytes and monocytes. Also, the response of both cell types to licensing with tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) was examined using these methods. As apoptosis of implanted MSC as a mode of action of MSC has gained more interest in recent literature, the role of apoptosis derived and secreted apoptotic bodies was assessed. The apoptotic bodies from naïve and licensed MSC or iMSC were first isolated and characterised. Next, the apoptotic bodies’ ability to repair OA cartilage, reduce T lymphocyte proliferation, polarise M1 macrophages to their M2 phenotype and miRNA cargo was investigated. Here, we show that the MSC and iMSC, although not identical, are similar in their ability to differentiate, secrete anti-inflammatory factors and modulate the immune system. Likewise, the apoptotic bodies from untreated MSC and iMSC shared similar but not identical characteristics. Also, we demonstrated that licensing with inflammatory factors does improve the immunomodulatory capacity of MSC, iMSC and their apoptotic bodies. Further analysis and in vivo studies will be required to validate these findings. Still, in vitro iMSC behave similarly to MSC, with variations similar to that seen for MSC from alternative sources. iMSC offer greater expandability, reduced cost, and reduced heterogeneity. Additionally, licencing is a realistic alternative approach to improve MSC efficacy. iMSC and licensing may improve the clinical outcome of MSC trials and, therefore, bridge the gaps from clinical trials to the market for MSC cell therapy.
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University of Galway
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Attribution-NonCommercial-NoDerivatives 4.0 International