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 factor (HGF/SF) in the growth and/or differentiation of pancreatic islet beta-cells. We found that in the human fetal pancreas immunoreactive HGF/SF receptor (c-met proto-oncogene product) is preferentially associated with the developing beta-cells. In the adult pancreas, c-met messenger RNA is highly enriched in the islets and the immunoreactive protein is also restricted to the islet beta-cells. HGF/SF messenger RNA content of fetal pancreas-derived fibroblasts is more than 10-fold higher than that of adult fibroblasts. Culture of human fetal pancreatic epithelial cells in conditioned medium from the fetal pancreatic fibroblasts 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 the conditioned medium, and this was associated with a marked decrease in insulin content. All of the effects of the conditioned medium were blocked by anti-HGF/SF antibody. Specificity was confirmed by overriding 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-cell replication. These results suggest that HGF/SF secreted by fetal fibroblasts is mitogenic to beta-cells. Taken together, our findings indicate an important role for HGF/SF in fetal mesenchyme-induced pancreatic beta-cell growth.
Otonkoski
T
T
The Whittier Institute, Department of Pediatrics, University of California San Diego, La Jolla, 92037.
Cirulli
V
V
Beattie
M
M
Mally
M I
MI
Soto
G
G
Rubin
J S
JS
Hayek
A
A
D000328:Adult; D000704:Analysis of Variance; D002455:Cell Division; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D005333:Fetus; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005455:Fluorescent Antibody Technique; D005865:Gestational Age; D005934:Glucagon / Q000032:analysis / Q000096:biosynthesis; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000032:analysis / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology / Q000502:physiology*; D008648:Mesoderm / Q000502:physiology*; D018613:Microscopy, Confocal; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met; D012333:RNA, Messenger / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic
D017077:Culture Media, Conditioned; D007328:Insulin; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; D005934:Glucagon; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases