Induction of beta 1 integrin synthesis by recombinant platelet-derived growth factor (PDGF-AB) correlates with an enhanced migratory response of human dermal fibroblasts to various extracellular matrix proteins.

Cell migration plays a major role during wound healing and is tightly controlled by a variety of growth factors and extracellular matrix proteins. The experiments reported here have been designed to study whether defined beta 1 integrins are involved in the platelet-derived growth-factor-AB (PDGF-AB)-modulated migratory response to collagen type I and to fibronectin. Preincubation of fibroblasts with PDGF-AB resulted in an up to 2.5-fold increase in the migratory response to collagen type I as well as fibronectin and to enhanced synthesis and cell surface expression of the alpha 2, alpha 3, alpha 5, and beta 1 integrin subunits. Function-blocking monoclonal antibodies against the common beta 1 integrin subunit dose-dependently inhibited the PDGF-AB-augmented migration of fibroblasts to collagen type I and fibronectin. The PDGF-AB-induced migration to collagen type I was also inhibited by antibodies against the alpha 2 integrin subunit, whereas the corresponding migration to fibronectin was almost completely blocked by the combined application of antibodies against the alpha 3 and the alpha 5 integrin subunits. Taken together, up-regulation of integrin synthesis and expression by human recombinant PDGF-AB correlate with an increase in the migratory response of dermal human fibroblasts to various extracellular matrix proteins and thus may contribute to an efficient regulation of cell migration during wound healing and tissue repair.

Localization of platelet-derived growth factor receptor subunit expression in chronic venous leg ulcers.

Cellular responses to platelet-derived growth factor, which affects all phases of the wound healing process, are dependent on the interaction of the growth factor with its cell surface receptors. Recently, we have shown that the platelet-derived growth factor-receptor was not expressed in uninjured human skin. In acute human wounds healing by secondary intention, both platelet-derived growth factor-receptor subunits were coordinately expressed, whereas no expression was found after reepithelialization at day 47. Even though impaired wound healing may be due to uncoordinated expression or the failure to express platelet-derived growth factor-receptor subunits, little is known regarding their expression in chronic ulcers. We studied the localization of platelet-derived growth factor-receptor expression in chronic venous leg ulcers of 15 patients with a median age of 73 years. Cryostat sections of biopsy specimens were immunostained with the use of antibodies against the alpha- and the beta-platelet-derived growth factor subunits. RNA was extracted from biopsy specimens and subjected to Northern blot analysis with the use of oligolabeled complementary DNA for the platelet-derived growth factor-receptor. Platelet-derived growth factor-receptor alpha- and beta-subunit expression was found in fibroblast-like cells within the wound bed and in cells beneath the epidermis of the wound edge. Platelet-derived growth factor-receptor beta-subunit expression was detected in endothelial cells of the vessels, in the granulation tissue, and the wound edge, whereas platelet-derived growth factor-receptor alpha-subunit was not expressed in endothelial cells of the uninjured skin. This finding suggests that the platelet-derived growth factor alpha-subunit may be involved in vessel formation during tissue repair. Both platelet-derived growth factor-receptor subunits were expressed at the messenger RNA level indicating that the synthesis is at least partly regulated at a pretranslational level. As the cellular responsiveness to growth factors depends on their specific receptors, our finding that both platelet-derived growth factor-receptor subunits are expressed in chronic venous ulcers substantiates the concept of therapeutic trials with recombinant platelet-derived growth factor.