Advances in repair are directed at optimizing chronic wound closure and preventing excess scarring. Growth factors enhancement of chronic wound closure has been disappointing and little progress has been made in preventing or resolving excess scar. An alternative way of optimizing repair is to identify and to understand the process that synchronizes the homogeneous fibroblast populations with their characteristic phenotypes, during normal wound healing. Examples of wound fibroblast phenotypes include the migrating, the synthetic, the myofibroblast and the apoptotic fibroblast. In contrast, the fibroblast populations composing chronic wounds and excess scars are made up of heterogeneous fibroblast phenotypes. Do alterations in the synchronization of wound fibroblast changes in phenotypes contribute to retarded or excessive repair? The hypothesis is gap junctional intercellular communications (GJIC) synchronize the phenotypic changes associated with wound fibroblasts in normal repair. Gap junction channels are composed of membrane embedded connexons, which contain 6 connexin (Cx) proteins, which directly connect the cytoplasm of coupled cells. Small molecules passing through gap junction channels can alter cell physiology. There is a family of Cx proteins, where fibroblasts contain mostly Cx43. Mast cells (MCs) have been implicated in excess fibrosis. We reported GJIC between MCs and fibroblasts enhances co-cultured MC-fibroblast populated collagen lattices contraction. With human fibroblasts we will show that heterotrophic GJIC between MCs and fibroblasts increase collagen synthesis; transform fibroblasts into myofibroblasts, promote connective tissue compaction (scar contracture) and reduce myofibroblasts entrance into apoptosis: In rats we will demonstrate inhibiting GJIC and/or Cx43 expression retards granulation tissue development, while promoting GJIC and Cx43 expression escalates granulation tissue maturation. Uncoupler treated human fibroblasts show impaired collagen synthesis. Is that inhibiton of collagen synthesis by blocking GJIC through a mechanism of impaired procollagen transport or by eliminating the transcription of the procollagen gene? The objectives of the proposal are to document the importance of GJIC in advancing normal repair and minimizing excess scarring.
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