Expression of gastrin and transforming growth factor-alpha during duct to islet cell differentiation in the pancreas of duct-ligated adult rats

In adult rats islet cell neogenesis can be stimulated by partial duct ligation. Duct to islet cell differentiation is thought to be regulated by growth factors such as gastrin and transforming growth factor-alpha (TGF alpha). To test this hypothesis, we examined the expression of gastrin and TGF alpha at the mRNA and protein level in pancreatic tissue following partial duct ligation. Pancreatic specimens were investigated on days 3, 5, 7 and 14 after duct ligation by means of non-isotopic in situ hybridization, immunocytochemistry and Western blotting. Gastrin mRNA was strongly expressed in newly developed duct-like cell structures in the ligated tail portion of the pancreas before the period of pronounced islet cell neogenesis (days 5 and 7), and immunostaining for gastrin peptides was positive at days 5-7. In the non-ligated head portion and in control pancreases, gastrin was not expressed. Expression of TGF alpha was found to be increased in the ligated tail portion of the pancreason day 3 and particularly on day 5, while there was no enhanced signal in the non-ligated part. Western blotting revealed two different TGF alpha isoforms (18 kDa and 42 kDa) in the ligated tail part and three isoforms (18 kDa, 24 kDa and 42 kDa) in the non-ligated head part and in untreated pancreases. The induction of gastrin and TGF alpha expression preceded the peak in the bromodeoxyuridine pulse labelling index of beta cells, known from a previous study to occur on day 7. We conclude that pancreas duct ligation induces the overexpression of gastrin and TGF alpha in the first days following ligation. Since ductal cells are known to give rise to endocrine cells after duct ligation, gastrin and TGF alpha may play a role as growth factors in islet neogenesis.