Evaluation of matricellular proteins as potential therapeutics for the treatment of human chronic skin wounds
Doctor of Philosophy
Anatomy and Cell Biology
Douglas W. Hamilton
There is currently an unmet need for treatments to enhance healing of human chronic skin wounds. Previously, therapy development has focused on growth factors and physical matrices, often resulting in disappointing clinical outcomes. In this thesis, we approached chronic skin wound treatment with a focus on fibrosis and matricellular proteins. Fibrosis is a pathological condition where tissue repair continues, unchecked, resulting in excess contraction, matrix accumulation and fibrogenic growth factor activity; features critically reduced in chronic skin wounds. Identifying factors that promote fibrosis may offer new therapeutic targets for use in chronic skin wounds. Two such factors are the matricellular proteins periostin and CCN2. As a group, matricellular proteins have established roles in acute wound healing; facilitating growth factor signaling, matrix production and contraction. However, as of yet, matricellular proteins represent an uninvestigated resource for modulating chronic skin wound healing. The objective of this thesis was to determine the potential of periostin and CCN2 as therapeutics for accelerating skin wound healing. Periostin is up-regulated during skin healing but its function was unknown. Using periostin knockout mice, we observed a delay in fullthickness excisional wound closure in the absence of periostin. This delay was attributed to a lack of myofibroblast differentiation, central to wound contraction, both in vivo and in vitro. Next we examined the expression patterns of periostin and CCN2 in tissue samples from human chronic skin wounds. Within these wounds CCN2 was not induced and periostin was decreased. These expression patterns were likely due to the environment of the wounds since fibroblasts cultured from wound tissue expressed periostin and CCN2, responded to TGFβ, proliferated and contracted collagen gels; consistent with a fibrotic phenotype. Using a mouse model of impaired diabetic skin healing, we found that delivery of recombinant periostin or CCN2 accelerated wound healing. The mechanisms through which periostin and CCN2 delivery influenced wound healing were distinct, and combination of the two treatments produced synergistic outcomes. These findings represent the first report of using matricellular proteins to enhance healing of diabetic skin wounds in an animal model, with an aim to improve healing of human chronic skin wounds.
Elliott, Christopher G., "Evaluation of matricellular proteins as potential therapeutics for the treatment of human chronic skin wounds" (2013). Electronic Thesis and Dissertation Repository. 1501.