PAX4 Gene Transfer Induces α-to-β Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment

The transcription factor Pax4 plays a critical role in the determination of alpha-versus beta-cell lineage during endocrine pancreas development. In this study, we explored whether Pax4 gene transfer into alpha-cells could convert them into functional beta-cells and thus provide therapeutic benefits for insulin-deficient diabetes. We found that Pax4 delivered by adenoviral vector, Ad5.Pax4, induced insulin expression and reduced glucagon expression in alpha TC1.9 cells. More importantly, these cells exhibited glucose-stimulated insulin secretion, a key feature of functional beta-cells. When injected into streptozotocin-induced diabetic mice, Pax4-treated alpha TC1.9 cells significantly reduced blood glucose, and the mice showed better glucose tolerance, supporting that Pax4 gene transfer into alpha TC1.9 cells resulted in the formation of functional beta-cells. Furthermore, treatment of primary human islets with Ad5.Pax4 resulted in significantly improved beta-cell function. Detection of glucagon(+)/Pax4(+)/Insulin(+) cells argued for Pax4-induced alpha-to-beta cell transitioning. This was further supported by quantification of glucagon and insulin bi-hormonal cells, which was significantly higher in Pax4-treated islets than in controls. Finally, direct administration of Ad5.Pax4 into the pancreas of insulin-deficient mice ameliorated hyperglycemia. Taken together, our data demonstrate that manipulating Pax4 gene expression represents a viable therapeutic strategy for the treatment of insulin deficient diabetes.