Effects of Activin A on Pancreatic Ductal Cells in Streptozotocin-Induced Diabetic Rats

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Abstract
The shortage of islets for transplantation has led to find alternative insulin producing cells. Pancreatic progenitor cells in the duct have the potential to grow and differentiate into endocrine cells. In this study, we examined whether activin A can promote the expansion and/or differentiation of ductal cells into insulin-producing cells.Pancreatic ductal cells were treated with activin A for differentiation into endocrine cells, and transplanted into the renal subcapsular space of streptozotocin (STZ)-induced diabetic rats. The identity of the endocrine cells was confirmed by immunostaining and analysis of the expression of transcription factors and endocrine genes by reverse-transcriptase polymerase chain reaction.Activin A treatment significantly increased the DNA synthesis and the expression of insulin I, insulin II, PDX-1, Nkx 6.1, Glut-2, Pax-4, Pax-6, and Ngn-3. De novo synthesis of insulin in activin A-treated ductal cells was observed by the immunocytochemical detection of C-peptide and the differentiated ductal cells secreted significantly increased amount of insulin compared to nontreated ductal cells in response to glucose stimulation. When activin A-treated ductal cells were transplanted on STZ-induced diabetic rats, blood glucose levels were normalized and the removal of the transplanted kidney resulted in return to hyperglycemia.The pancreatic ductal cells could be efficiently differentiated into insulin secreting cells by activin A treatment in vitro and normalize hyperglycemia in vivo.