Following injury, fibroblasts migrate into the wound bed, where they play essential roles in effective wound healing through matrix deposition and contraction. Fibroblast migration relies on cell-matrix and cell-cell contacts, both of which are regulated by transmembrane receptors that are differentially regulated during wound healing. The fibronectin receptor syndecan-4 is increased upon wounding, which promotes fibroblast migration through activation of small GTPases and the recycling of integrin a5~1. Members of the Eph family of receptor tyrosine kinases, which regulate cellcell contacts, are also differentially regulated upon wounding. Little is known about whether there is a relationship between the syndecan-4 and Eph receptors, and how this might regulate the balance between cell -cell and cell-matrix contacts, and therefore fibroblast migration and clustering. Using transient knockdown and genetic knockout models, this project demonstrates that syndecan-4 downregulates EphA2, a receptor that mediates cell-cell repulsion, through a PKCa- and Fyn-dependent mechanism. In syndecan-4 knockout mouse embryonic fibroblasts, elevated EphA2 expression increases sensitivity to the EphA2 ligand ephrinA 1 and increases the rate and frequency of cell-cell repulsion when compared to wild type, demonstrating that the relationship between syndecan-4 and EphA2 has a direct effect on fibroblast clustering. Importantly, the findings are translated in vivo; EphA2 expression is increased in syndecan-4 knockout mouse wounds compared to wild type. This may contribute to the healing defect previously observed in syndecan-4 knockout mice 1. We hypothesise that the balance between syndecan-4 and EphA2 signalling regulates the switch between fibroblast clustering or scattering, and therefore coordinates the initiation and resolution of healing.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:690373 |
| Date | January 2016 |
| Creators | Brooks, Rebecca |
| Publisher | University of Bristol |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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