A ROLE FOR HEPATOCYTE GROWTH FACTOR SCATTER FACTOR IN FETAL MESENCHYME-INDUCED PANCREATIC BETA-CELL GROWTH/

We have investigated the role of hepatocyte growth factor/scatter fact or (HGF/SF) in the growth and/or differentiation of pancreatic islet b eta-cells. We found that in the human fetal pancreas immunoreactive HG F/SF receptor (c-met proto-oncogene product) is preferentially associa ted with the developing beta-cells. In the adult pancreas, c-met messe nger RNA is highly enriched in the islets and the immunoreactive prote in is also restricted to the islet beta-cells. HGF/SF messenger RNA co ntent of fetal pancreas-derived fibroblasts is more than 10-fold highe r than that of adult fibroblasts. Culture of human fetal pancreatic ep ithelial cells in conditioned medium from the fetal pancreatic fibrobl asts caused a 2.4-fold stimulation of the formation of islet-like cell clusters that was due to both mitogenic and morphogenic effects. beta -cell proliferation in the cell clusters was stimulated 3.5-fold by th e conditioned medium, and this was associated with a marked decrease i n insulin content. All of the effects of the conditioned medium were b locked by anti-HGF/SF antibody. Specificity was confirmed by overridin g the blocking effect of the antibody with excess recombinant HGF/SF. Conditioned medium from adult pancreatic fibroblasts stimulated islet- like cell cluster formation only slightly, and did not affect beta-cel l replication. These results suggest that HGF/SF secreted by fetal fib roblasts is mitogenic to beta-cells. Taken together, our findings indi cate an important role for HGF/SF in fetal mesenchyme-induced pancreat ic beta-cell growth.