The therapeutic role of fibronectin in the re-epithelialization response following wounding in a human skin/mouse xenografting model

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Abstract The atopic environment diminishes wound re-epithelialization and the defect in the wound healing process is IL-4 dependent. IL-4 represses fibronectin secretion from keratinocytes and impairs the ability of keratinocytes in culture to migrate into a scratch and to close a wound in vivo. Addition of fibronectin to culture increased closure of the scratch assay in vitro and re-epithelialization of wound tissue in vivo when fibronectin was applied topically. In this study, a human skin/mouse xenografting model was used to test the ability of IL-4 to impair re-epithelialization in human skin and to test whether fibronectin can mitigate the effects of IL-4. Human skin was grafted onto immunodeficient SCID/NOD mice. Approximately 10–12 weeks post-transplantation, human skin was fully integrated onto the mouse. A shallow punch biopsy was performed on the human skin to generate a wound that did not penetrate into mouse tissue. Human IL-4 was intravenously injected twice a week before the punch and recombinant fibronectin was spread over the wound twice daily after the wounding. Anatomic wound healing was monitored, and EDC gene expression and skin histology were assessed. Our results showed that mice injected with human IL-4 had delayed wound healing, decreased human EDC gene expression and increased MMP19 and CCL26 expression in human skin tissue. Treatment of skin with fibronectin attenuated the effect of IL-4 on human gene expression and promoted wound healing and re-epithelialization. These results suggest that fibronectin has a potential therapeutic role in the treatment of atopic lesions. Supported by grants from NIH (R01AI095282)

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