Taki, Zeinab Ahmad; (2018) Modelling the Interaction Between the Disease Microenvironment and Mesenchymal Stem Cells in Systemic Sclerosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Systemic sclerosis (SSc) is a complex autoimmune disease with unknown aetiology. While the presence of auto-antibodies classifies this disease as autoimmune, the issues concerning this disease extend much further with particular respect to inflammation and the gradually progressing internal and external organ fibrosis. If not lethal, at the very least, the symptoms of SSc are life-altering. Many potential driving forces are hypothesised to exacerbate pathology, one of which is the microenvironment in lesional skin, in which resident mesenchymal stem cells (MSCs), are exposed to aberrantly expressed growth factors and cytokines, and excessively stiffened and abundant extracellular matrix. In this thesis, it is hypothesised that MSCs adopt a pro-fibrotic, chronic, wound healing phenotype in response to the disease microenvironment. Different representations of the disease microenvironment were assessed, including patient blister fluid, and some of its individual components, IL31 and lactate, in addition to the physical stiffness of the microenvironment. MSCs cultured in these conditions were assayed for migration, induced gel contraction, pro-fibrotic gene expression and differentiation. The presence of activated MSCs in patients’ skin was also assessed and compared with healthy skin. Patient blister fluid induced MSC migration, collagen gel contraction and pro-fibrotic gene expression more than healthy blister fluid. Additionally, individual components of the SSc blister fluid accounted for at least some of these responses. Osteogenic differentiation of MSCs was enhanced by SSc microenvironments, both soluble and physical, whereas adipogenic differentiation was inhibited. Next-generation sequencing of treated MSCs highlighted fibrogenic and inflammatory pathways upregulated by SSc blister fluid. The role of MSCs in SSc pathogenesis was until now relatively unexplored. The results of this thesis give new insight into the pathological part MSCs play in this disease and highly implicate MSCs in SSc related fibrosis, wound healing, tissue scarring and remodelling, calcinosis and loss of subcutaneous fat.

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