Medicine (St Vincent's) - Theses

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    The potential role of inflammatory cells in neoadipogenesis
    Galea, Laurence Aaron ( 2010)
    Reconstruction of soft tissue defects presents a major challenge in clinical practice. Current treatment strategies for large and small volume replacement of such defects are less than satisfactory. Generation of endogenous stable vascularized adipose tissue engineered constructs can have an enormous clinical impetus. In order to study adipose tissue engineering in vivo, a mouse tissue engineering model that consists of a ‘sealed’ silicone chamber supplied with a dedicated flow-through epigastric pedicle and incorporating Matrigel matrix supplemented with fibroblast growth factor-2 was developed at the O’Brien Institute. Previous research using this model revealed that sealed chambers containing just matrix resulted in minimal adipogenesis. However, when a viable free fat graft was inserted into the chamber together with the matrix, resulted in significant vascularized adipose tissue in the chamber that was subsequently found to be host-derived. The free graft was mostly necrotic and was infiltrated by inflammatory cells. When the graft was replaced by the sterile inflammagen zymosan, adipogenesis was induced in an inverse dose-dependent manner. This data supports several studies that link adipogenesis and inflammation in obesity. Mast cells and macrophages are important inflammatory cells that participate in inflammatory responses and may be related to endogenous adipogenesis. They also participate in angiogenesis which is closely related to adipogenesis. The potential roles of mast cells and macrophages in angiogenesis and adipogenesis were investigated using this mouse tissue engineering model. This was performed using two mast cell-deficient mouse strains and knocking out macrophages in another strain using clodronate liposomes. Mast cells were not found to be important in angiogenesis and adipose tissue development in this model, though there was a significant strain difference in fat development. On the other hand, macrophages play a critical role in both angiogenesis and adipose tissue development in this model. Normal white adipose tissue is innervated by sympathetic nerve fibres that have important physiological functions. There is a neuroimmune link between sympathetic nerve fibres, nerve growth factor and inflammatory cells such as mast cells and macrophages. Sympathetic nerve regeneration in the mouse tissue engineering model was described in this thesis. Sympathetic nerves did not correlate with the mast cell numbers and inversely correlated with macrophage density at six weeks. However, sympathetic nerve regeneration positively correlated with the percentage of new adipose tissue developed. Further in vitro studies revealed that both undifferentiated and differentiated stromal vascular fraction induced neurite outgrowth from SCG suggesting that cells, possibly preadipocytes, differentiated adipocytes, vascular endothelial cells and inflammatory cells may support sympathetic nerve development in the chamber. This thesis identifies the importance of macrophages and the insignificance of mast cells in vascularized adipose tissue development. It also describes sympathetic nerve regeneration in association with vascularized adipose development.