Expression of transcription factors and precursor cell markers during regeneration of beta cells in pancreata of rats treated with streptozotocin.

An understanding of beta cell regeneration is needed if we are to develop new treatment modalities in diabetes mellitus. Lineage tracing studies have shown that all pancreatic cell types, including beta cells, arise from PDX-1-expressing precursor cells. We studied beta cell regeneration by analyzing the immunocytochemical expression of the transcription factors, PDX-1, PBX-1, and MEIS2, and that of the potential precursor cell markers, c-Kit and nestin, using the model of streptozotocin (STZ)-induced diabetes in rats. The pancreata were examined 3, 7, and 14 days after STZ administration. PDX-1 expression, but not that of MEIS2 and PBX-1, transiently increased on day 7. c-Kit expression was found to be upregulated in islet cells at all points in time, while nestin expression was lacking. Ki-67 labeling was increased in islets on days 3 and 7. These results suggest that temporary upregulation of PDX-1 and prolonged overexpression of c-Kit may play a role during beta cell regeneration.

Expression of stem cell markers and transcription factors during the remodeling of the rat pancreas after duct ligation.

Ligation of the pancreatic duct has been shown to induce islet cell neogenesis from duct cells in the adult rat pancreas. The transcription factors that regulate islet cell neogenesis and the phenotype of putative precursor cells involved in neogenesis are unknown. We, therefore, studied the expression of the transcription factors Pdx1, Pbx1, Meis2, Nkx2.2 and the putative stem cell markers c-Kit and nestin in rat pancreata 3, 5 and 7 days after duct ligation. Immunocytochemical staining revealed a subpopulation of cells in the ligated portion of the pancreas that was positive for the putative stem cell markers c-Kit and nestin. The c-Kit immunoreactivity was upregulated, reaching a peak at day 3, while nestin expression peaked at day 7. The c-Kit-positive cells were located among the duct and islet cells, while nestin-expressing cells were found scattered in the duct epithelium at day 3 and around the ducts at day 7. Both c-Kit- and nestin-positive cells showed high proliferative activity, as determined by BrdU labeling. Pdx1 and Nkx2.2 were found predominantly in the duct cells of the ligated pancreas. There were significant changes in the expression patterns of Pbx1 and Meis2 in the ductular complexes. The findings indicate that the stem cell markers c-Kit and nestin as well as the transcription factors Pdx1 and Nkx2.2 are upregulated in compartments of the pancreas that are involved in islet cell neogenesis after duct ligation.