Hepatocyte growth factor/scatter factor has insulinotropic activity in human fetal pancreatic cells.
Fetal mesenchyme-derived factors are likely to play an important role in pancreatic islet development and growth. We have used primary cultures of human fetal pancreatic tissue to identify growth factors that have morphogenic, mitogenic, and insulinotropic activity. The formation of islet-like cell clusters (ICCs) during a 6-day culture was stimulated two- to threefold by hepatocyte growth factor/scatter factor (HGF/SF) basic fibroblast growth factor (FGF)-2, and to a lesser extent by keratinocyte growth factor (FGF-7) and insulin-like growth factor-II (IGF-II). In contrast, transforming growth factor-beta (TGF-beta) had a strong inhibitory effect. The ICCs formed during HGF/SF stimulation consisted mainly of epithelial cells, whereas FGF-2-induced ICCs were predominantly nonepithelial. Furthermore, although both FGF-2 and HGF/SF increased the total insulin content of the cultures, only HGF/SF increased the insulin content per DNA. Quantitatively, HGF/SF stimulated a 2.3-fold increase in the proportion of insulin-positive cells and a 3-fold higher number of replicating beta-cells. Blocking of the IGF-I receptor inhibited ICC formation but did not affect their insulin content. Immunoneutralizing TGF-beta resulted in increased cell growth and insulin content, indicating the presence of an endogenous inhibitory TGF-beta activity in the model system. Our results suggest that HGF/SF may be an important component of the fetal mesenchyme-derived factors responsible for pancreatic islet development. HGF/SF also may prove valuable for supporting the in vitro growth of islet cells.
Lucy Thorne Whittier Children's Center, La Jolla, California.
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T
Otonkoski
G M
GM
Beattie
J S
JS
Rubin
A D
AD
Lopez
A
A
Baird
A
A
Hayek
D000029:Abortion, Legal; D000704:Analysis of Variance; D000906:Antibodies / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D005333:Fetus; D005865:Gestational Age; D006133:Growth Substances / Q000494:pharmacology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000196:embryology / Q000502:physiology*; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000196:embryology*; D011247:Pregnancy; D017526:Receptor, IGF Type 1 / Q000276:immunology / Q000502:physiology; D013936:Thymidine / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000502:physiology
D000906:Antibodies; D000911:Antibodies, Monoclonal; D006133:Growth Substances; D007328:Insulin; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; D004247:DNA; D017526:Receptor, IGF Type 1; D013936:Thymidine