MATRIX REGULATION OF CELL FUNCTION DURING WOUND HEALING

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DESCRIPTION: (Adapted from the applicant's abstract) Wound scarring and contracture is an important clinical problem with potentially serious consequences for the surgical or burn patient, including impairment of normal tissue regeneration and neighboring tissue function. The scarring that is a hallmark of normal wound healing occurs as a consequence of finely regulated interactions between fibroblasts cytokines, growth factors, proteases and extracellular matrix molecules. The long term goal is to understand this regulatory mechanism and develop new therapies to control scarring. The fibronectins (FNs), present in low levels in most normal tissues, are adhesive glycoproteins that mediate important functions, in vitro, such as cell activation, proliferation and migration. The investigators demonstrate that a dramatic increase in the levels of FNs occurs at the wound site, first by extravasation of plasma FN from blood, and then from synthesis by wound cells, making FNs as prominent components of the wound matrix. Two alternatively spliced segments, termed EIIIA or EIIIB, included in certain FN variants are expressed prominently in FNs present during embryogenesis. These two segments are missing from normal plasma FN and are present at low levels in most normal adult tissues. They find that expression by wound cells of FN variants that include the EIIIA and EIIIB segments is dramatically upregulated following injury in a characteristic spatial and temporal pattern. Moreover, parallel patterns of EIIIA+FNs and SMC a-actin expression occur during cutaneous wound healing. These findings suggest that the FN-containing wound matrix supplies a critical regulatory function in governing wound cell function. Indeed, when tested in vitro, FN variants that include the EIIIA segment activate fibroblasts to express increased levels of SMC a-actin. The specific hypothesis of the present proposal states that adhesion of fibroblasts to the EIIIA segment of FN provides a key signal, which together with cytokines like TGF-b, regulate the activity of fibroblasts during scar formation. Two specific aims are proposed to test this hypothesis: (1) To determine the structural features within EIIIA+FNs that regulate fibroblasts functions; (2) To analyze specific fibroblast functions regulated by EIIIA+FNs.