T. Otonkoski et al., A ROLE FOR HEPATOCYTE GROWTH FACTOR SCATTER FACTOR IN FETAL MESENCHYME-INDUCED PANCREATIC BETA-CELL GROWTH/, Endocrinology, 137(7), 1996, pp. 3131-3139
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.