Hepatocyte growth factor and macrophage-stimulating protein are upregulated during excisional wound repair in rats

Hepatocyte growth factor (HGF) and macrophage- stimulating protein (MSP) ar e structurally related molecules that stimulate epithelial cell proliferati on and migration. MSP also acts directly as a chemoattractant for resident macrophages. These activities are integral to the wound repair processes of inflammation, epithelialization and tissue remodelling. To begin to examin e the involvement of HGF and MSP in healing of cutaneous wounds we have map ped the temporal expression of these two molecules and their receptors, MET and RON respectively, in adult rat excisional wounds. Four 2x2-cm full-thi ckness excisional wounds were created on the dorsum of 18 rats, and biopsie s were taken through the wounds at 3, 5, 7, 14, 21, and 28 days postwoundin g. These biopsies were analyzed using immunofluorescent staining and in sit u hybridization (ISH). The number of cells staining positively for HGF and MET significantly increased in response to wounding. HGF staining and mRNA peaked at 7 days postwounding whereas MET was upregulated earlier, peaking after 3 days. Both HGF and MET protein were observed in fibroblasts of the dermis and in the newly forming granulation tissue. ISH studies also reveal ed that fibroblasts at the wound edges and within the newly forming granula tion tissue also expressed HGF and c-met mRNA. Immunofluorescent staining r evealed both MSP and RON within the wound, with maximum staining occurring between 7 and 21 days for both the ligand and receptor. In addition, MSP co localized with a small subset of EDI-positive cells (monocytes). In contras t, ED2-positive cells (macro- phages) did not co-localize with MSP. Thus, i ncreased expression of HGF, MSP and their receptors MET and RON respectivel y was observed in response to wounding. Furthermore, MSP co-localization wi th a subset of monocytes may confirm a role for MSP in the activation of ma ture macrophages, which may be important in tissue remodelling.