Final Activity Report Summary - MDDI (Dynamic studies of the wound-triggered inflammatory response and associated fibrosis and scarring)
Wound repair is a highly ordered, multi-step process involving cell and tissue migration leading to rapid closure of the wound and subsequent regeneration of the injured tissue. There is an inflammatory response upon wounding; whereby white blood cells and the body's other defences are activated to protect us from infection or foreign bodies. Unfortunately, this inflammatory response can become a clinical problem itself - the Martin lab has previously shown that in the absence of an inflammatory response, wound healing can occur perfectly, without scarring, and so we think that inflammatory cells contribute to the negative side-effects of tissue repair, such as fibrosis and scarring. The main aims of this project were to analyse the effects of inflammatory cells on other cell types within the wound and to investigate whether decreasing the expression of specific inflammation-induced genes could improve the quality of wound repair.
In order to study the effects of inflammatory cells on other cells resident in the wound, such as fibroblasts, I took a co-culture approach with the two cell types. Time-lapse microscopy revealed that fibroblasts cultured in the presence of inflammatory cells underwent a striking change in cell shape with a decrease in size, and retraction of cell-cell contacts. Moreover, fibroblasts were less adhesive and less motile in the presence of inflammatory cells. These finding would help us improve our understanding of how the wound inflammatory response affects the behaviour of other cells types and may exacerbate fibrosis and scarring.
We were also interested in the effects of inflammatory cells on the gene expression profile of wound fibroblasts. Our lab recently compared the genes expressed in normal wound tissues with wounds from mice lacking inflammatory cells and a number of inflammation-dependent genes were identified. Osteopontin (OPN) was such a gene, expressed only in wound fibroblasts in the presence of inflammation. It was a multi-functional protein implicated in pulmonary, cardiac and renal fibrosis, and it was our hypothesis that OPN contributed to fibrosis and scarring during the repair process. We suppressed OPN expression in wounds and excitingly found that this led to accelerated healing and reduced scarring.
Despite its negative side effects, inflammation is very important for its role in protecting the body from infection, but it will be perhaps possible in the future to clinically inhibit only its unwanted consequences. For example, based on our findings, we suggested that osteopontin may prove to be a valuable therapeutic target to improve healing rate and quality during skin repair.
In order to study the effects of inflammatory cells on other cells resident in the wound, such as fibroblasts, I took a co-culture approach with the two cell types. Time-lapse microscopy revealed that fibroblasts cultured in the presence of inflammatory cells underwent a striking change in cell shape with a decrease in size, and retraction of cell-cell contacts. Moreover, fibroblasts were less adhesive and less motile in the presence of inflammatory cells. These finding would help us improve our understanding of how the wound inflammatory response affects the behaviour of other cells types and may exacerbate fibrosis and scarring.
We were also interested in the effects of inflammatory cells on the gene expression profile of wound fibroblasts. Our lab recently compared the genes expressed in normal wound tissues with wounds from mice lacking inflammatory cells and a number of inflammation-dependent genes were identified. Osteopontin (OPN) was such a gene, expressed only in wound fibroblasts in the presence of inflammation. It was a multi-functional protein implicated in pulmonary, cardiac and renal fibrosis, and it was our hypothesis that OPN contributed to fibrosis and scarring during the repair process. We suppressed OPN expression in wounds and excitingly found that this led to accelerated healing and reduced scarring.
Despite its negative side effects, inflammation is very important for its role in protecting the body from infection, but it will be perhaps possible in the future to clinically inhibit only its unwanted consequences. For example, based on our findings, we suggested that osteopontin may prove to be a valuable therapeutic target to improve healing rate and quality during skin repair.