Neutralization of hepatocyte growth factor leads to retarded cutaneous wound healing associated with decreased neovascularization and granulation tissue formation

To elucidate biologic functions of hepatocyte growth factor and the c-Met receptor in cutaneous wound healing, we analyzed expression and localization of hepatocyte growth factor and c-Met receptor and used a strategy to neutralize endogenous hepatocyte growth factor in a cutaneous wound healing model in mice. Following excision of full-thickness skin on the dorsum of mice, expression of both hepatocyte growth factor and the c-Met receptor increased transiently in cutaneous tissues. Expressions of hepatocyte growth factor increased as early as 2 d postwounding and reached a peak on day 2, whereas the c-Met receptor expression reached a peak 2-4 d postwounding. Immunolocalization of the c-Met receptor indicated that c-Met receptor expression was upregulated in keratinocytes, vascular endothelial cells, and myofibroblasts in granulation tissue, hence these are potential target cells of hepatocyte growth factor. When normal rabbit IgG or neutralizing anti-hepatocyte growth factor IgG was locally and continuously delivered to subcutaneous lesions, the number of capillary vessels decreased with the neutralization of hepatocyte growth factor and there was an associated decreased expansion of granulation tissue. Likewise, retardation in re-epithelialization and the rate of wound closure occurred with neutralization of endogenous hepatocyte growth factor on days 4 and 7 postwounding. Therefore, hepatocyte growth factor is definitely involved in enhancing cutaneous wound healing processes, including re-epithelialization, neovascularization, and granulation tissue formation.