Endogenous electric fields (EFs) are present during a variety of physiologic and pathologic events, including penetrating injury to epithelial barriers. An applied electric field with strength within the physiologic range can induce directional cell migration of epithelial cells, endothelial cells, fibroblasts, and immune cells suggesting a potential role in controlling cell behaviours during wound healing. Dendritic cells (DCs) and dermal fibroblasts were used to explore the molecular mechanisms underlie EF-induced cell activities during two aspects of wound healing: immune response and remodelling. In this study, we investigated the effects of applied EFs on several types of DCs in response to IL18. DC progenitor cells KG-1 shows dose dependently response to EFs stimulation to increase IFN-γ expression. Moreover, the migration of KG-1-derived DCs and Langerhans cells (LCs) in mouse skin showed increased response to IL18 with directional migration when exposed to EFs in vitro and ex vivo. Furthermore, the in vivo investigation suggested that pharmacologically increased trans-epithelial potential difference (TEPD) induced LCs to emigrate from skin to draining lymph node. The sensitization of DCs to IL18 can be strengthened by EFs through redistribution of IL18 receptors and phosphorylation of p38 MAPK. We also comparatively studied the responses of human chronic wound fibroblast (CWF) and chronic matched fibroblast (CMF) to applied EFs with addition of platelet derived growth factor (PDGF). The results indicate that 1) EFs induce human dermal fibroblast directional migration in a voltage dependent manner. 2) CWF shows impaired sensitivity in response to EFs compared to CMF and HF. 3) Activation of PDGFR and PI3K are both required for EF-induced directional migration. 4) PDGF attenuates EF-induced migration directedness through PDGFR-ROCK other than PI3K pathway. 5) Optimised concentration of PDGF plus physiological EFs enhance chronic wound healing. We propose that the EF-induced re-distribution of the receptors on the cell surface results in a shift of membrane receptors between the cathode-facing and the anode-facing membrane of the cell. There would be a higher probability to overcome the threshold of signal transduction at the higher density receptor side. The downstream IV signalling cascade therefore can be ignited. Understanding the signalling pathways underlying guidance cues (EFs, cytokines, chemokines) will help to optimise future therapies for immunomodulation, vaccination, wound healing and regeneration.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:567467 |
| Date | January 2012 |
| Creators | Zhang, Gaofeng |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/42430/ |
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