Induction of PDX-1-positive cells in the main duct during regeneration after acute necrotizing pancreatitis in rats.

Abstract

Pancreatic regeneration involves two pathways; proliferation and differentiation of pancreatic progenitor cells, which probably exist in pancreatic ductal epithelium, and replication of pre-existing differentiated acinar, islet, and ductal epithelial cells. During pancreatic development, differentiated cells arise from the ductal progenitor cells expressing the pancreatic/duodenal homeobox-1 (PDX-1) homeodomain transcription factor. The aims of this study were to characterize cell proliferation and differentiation during regeneration after acute necrotizing pancreatitis and to evaluate the role of PDX-1-positive stem cells. Necrotizing pancreatitis was induced in rats by retrograde intraductal infusion of sodium taurocholate. Cell types were classified into five categories: main, large, and small ductal epithelial cells, tubular complexes and acinar cells. Each category was scored using a 5-bromo-2'-deoxyuridine (BrdU) labelling index (LI) at various time points after induction of pancreatitis. Tissue sections were also immunostained for PDX-1 to determine the source of pancreatic stem cells. Acinar necrosis was observed at 24 h after induction of pancreatitis and most lobules were filled with tubular complexes on day 5. Subsequently, newly formed acinar cells were observed on day 7, but the lobular architecture returned to normal appearance on day 28. Proliferation started in the main and large ducts at 24 h; marked mitotic activity was evident in small ductal epithelial cells and tubular complexes on day 3, and in acinar cells on day 7. At 24 h after induction of pancreatitis, epithelial cells of the main duct with PDX-1-positive nuclei were greatly increased, simultaneously with the peak LI of BrdU. These results suggest that regeneration after necrotizing pancreatitis involves proliferation and differentiation of pancreatic progenitor cells, and that ductal epithelial cells with PDX-1-positive nuclei may contribute to the differentiation of pancreatic stem cells in the main duct.