FORMATION OF INSULIN-PRODUCING CELLS FROM PANCREATIC ACINAR AR42J CELLS BY HEPATOCYTE GROWTH-FACTOR

Pancreatic AR42J cells are derived from acinar cells and express both exocrine and neuroendocrine properties. We have recently shown that th ese cells convert into insulin-producing cells in vitro after treatmen t with activin A and betacellulin. Here, we investigated the effect of hepatocyte growth factor (HGF) in those cells. When AR42J cells were incubated with HGF, DNA synthesis was attenuated, and the amylase cont ent was reduced in a concentration-dependent manner. HGF-treated cells extended processes, but bundle formation was not observed using an an tibody against tubulin. Reverse transcription-PCR analysis revealed th at messenger RNAs for both insulin and pancreatic polypeptide (PP) wer e expressed in HGF-treated, but not naive, AR42J cells. Immunocytochem ical analysis indicated that approximately 3% of the HGF-treated cells were stained with antiinsulin antibody, and some were also stained wi th anti-PP antibody. When AR42J cells were exposed to a combination of activin A and HGF, cells extended longer processes, and over 10% of t hem were stained with antiinsulin antibody. In these cells, messenger RNAs for insulin, PP, glucose transporter 2, and glucokinase, but not those for glucagon or somatostatin, were expressed. A subclone of AR42 J cells, AR42J-B13, was obtained. Most of the AR42J-B13 cells converte d to insulin-producing cells after the incubation with activin A and H GF. Insulin secretion was augmented by tolbutamide, depolarizing conce ntrations of potassium, carbachol, and glucagon-like peptide-1 in thes e cells. These results indicate that HGF reduces the acinar cell-like property of AR42J cells and converts them into insulin-producing cells . The effect of HGF was markedly enhanced by activin A.