GAP JUNCTIONAL COMMUNICATIONS IN WOUND HEALING
Principal Investigator: H Ehrlich
Affiliation: Pennsylvania State University
Abstract: 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.
Funding Period: 1999-01-01 - 2010-03-31
more information: NIH RePORT
- The myofibroblast, cadherin, alpha smooth muscle actin and the collagen effectH P Ehrlich
Division of Plastic Surgery, Irvin S Zubar Laboratory, Milton S Hershey Medical Center, Hershey, PA 17033, USA
Cell Biochem Funct 24:63-70. 2006..The other possibility is that the myofibroblast phenotype may be induced by factors other than mechano-tension...
- Gap junction communications influence upon fibroblast synthesis of Type I collagen and fibronectinH Paul Ehrlich
Irving S Zubar Laboratory, Division of Plastic Surgery, Department of Surgery, Hershey Medical Center, Hershey, Pennsylvania 17033 0850, USA
J Cell Biochem 98:735-43. 2006..The lack of connective tissue deposited in granulation tissues treated with uncouplers appears related to the inhibition of collagen synthesis. These findings suggest that altering GJIC might control collagen deposition in scarring...
- Elucidating the mechanism of wound contraction: rapid versus sustained myosin ATPase activity in attached-delayed-released compared with free-floating fibroblast-populated collagen latticesH Paul Ehrlich
Division of Plastic Surgery, Hershey Medical Center, Hershey, Pennsylvania 17033, USA
Wound Repair Regen 14:625-32. 2006..In contrast, the mechanism for ADR-FPCL contraction is through cell contraction by sustained myosin ATPase, involving tyrosine dephosphorylation...
- Does rat granulation tissue maturation involve gap junction communications?Katherine Au
Irving S Zubar Plastic Surgery Laboratory, Division of Plastic Surgery, Milton S Hershey Medical Center, Hershey, PA 17033, USA
Plast Reconstr Surg 120:91-9. 2007..Does added oleamide, a natural fatty acid that blocks gap junction intercellular communications, alter the phenotypic progression of wound fibroblasts?..
- Influence of vanadate on migrating fibroblast orientation within a fibrin matrixMichael Y Lee
Division of Plastic Surgery, Milton S Hershey Medical Center, Hershey, Pennsylvania, USA
J Cell Physiol 217:72-6. 2008..These findings support the notion that vanadate promotes the deposition of regular, parallel collagen fiber bundles by advancing the orientation of fibroblasts in parallel linear arrays early in the wound repair process...
- Mechanism of sustained release of vascular endothelial growth factor in accelerating experimental diabetic healingHarold Brem
Helen and Martin Kimmel Wound Center, Division of Wound Healing and Regenerative Medicine, Department of Surgery, New York University, New York, New York 10016, USA
J Invest Dermatol 129:2275-87. 2009..In the future, local administration and sustained, controlled release of VEGF(165) may decrease amputations in patients with diabetic foot ulcers and possibly accelerate closure of venous ulcers and pressure ulcers...