Optimizing the Immunoregulatory Properties of Human Mesenchymal Stromal Cells and their Extracellular Vesicles by Immunological Priming

This cumulative dissertation addresses the immunoregulatory properties of mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs). The research elucidates the molecular responses by MSCs when exposed to a multitude of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interferon-gamma (IFN-γ), thereby contributing to a deeper understanding of MSCs' immunoregulatory function. In the initial study, we compared the effects of TNF-α, IL-1β, and IFN-γ on MSCs, focusing on the augmented immunoregulatory response towards polymorphonuclear neutrophils (PMN). Our findings reveal a critical feedback loop where TNF-α and IL-1β enhance the expression of interferon-gamma receptor (IFN-γR) via nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB) signalling. This upregulation augments MSC responsiveness to IFN-γ, fostering an increased Interleukin 8 (IL-8) release and promoting the recruitment of PMN. Building upon this, the following study assessed the immunoregulatory properties of MSCs and their EVs, to enhance the immunosuppressive effects towards activated T cells and foster the induction of regulatory T cells in a (programmed cell death protein 1) PD-1 dependent manner. We demonstrated that EVs derived from primed MSCs not only attenuate the severity of graft-versus-host disease in a murine model but also prolong survival. In conclusion, this dissertation unveils priming strategies to potentiate the immunoregulatory functions of MSCs and their EVs, offering promising opportunities for the development of more effective MSC-based therapies.