Heparin as an Inducer of Hepatocyte Growth Factor1

Hepatocyte growth factor (HGF) has mitogenic and unique morphoregulatory functions, and is considered to act as a hepatotrophic and a renotrophic factor for regeneration of the liver and kidney subjected to various insults. We have now obtained evidence that heparin is a potent inducer of HGF production. The addition of heparin to a culture of MRC-5 human embryonic lung fibroblasts increased the HGF concentration in the conditioned medium, in a dose-dependent manner. The maximal stimulation was obtained at 1 /μg/ml heparin and stimulation was 4-fold compared to control cultures. The rate of HGF synthesis in MRC-5 cells, as measured by pulse-labeling with [35S]methionine, and subsequent immuno-precipitation of HGF from both conditioned medium and a cell lysate, was 3–4-fold stimulated by 1μg/ml.heparin,.whereas heparin apparently had no significant effect on the HGF mRNA level. The stimulatory effect of heparin on HGF production was evident in various types of cells, such as MRC-9, IMR-90, and WI-38 human embryonic lung fibro-blasts, human skin fibroblasts, HL-60 human promyelocytic leukemic cells and human umbilical vein endothelial cells. In addition to heparin, heparan sulfate also stimulated HGF production, albeit to a lesser extent than heparin; 1.7-fold stimulation with 2 /μg/ml heparan sulfate. However, other glycosaminoglycans, such as hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, and keratan polysulfate, had no stimulatory effect on HGF production. Interleukin-la (IL-lα) and 12-O-tetradecanoylphorbol-13-ace-tate (TPA) stimulated HGF production in human skin fibroblasts, and the simultaneous addition of heparin with EL-lα or TPA caused further marked enhancement of HGF production, in a synergistic manner. It would thus appear that heparin act as a potent inducer of HGF production by influencing post-transcriptional processes. We propose that heparin plays an important physiological role as an enhancer for tissue regeneration through its unique potential to stimulate HGF production.