Pax4 Gene Transfer Induces α-to-ß Transdifferentiation and Improves the Therapeutic Efficacy of Islet Transplantation

Pax4 is a transcriptional factor which plays a critical role in the generation of insulin producing β-cells during embryonic development. Our group previously demonstrated that Pax4 delivered by adenoviral vector induces insulin expression and reduces glucagon in αTC1.9 cells and primary human islets. The purpose of the present study was to determine whether Pax4 gene expression induces pancreatic α-cells to become β-cell using lineage tracing techniques and confers therapeutic benefits in the context of islet transplantation. In this study, we generated α mouse model in which their α cells are labelled with YFP, namely αYFP mouse. Using this mouse model, we found that Ad5.Pax4 induced glucagon secreting α-cells to become insulin secreting β-cells in isolated αYFP islets. Quantification of YFP + /Pax4 + /insulin + cells confirmed that Pax4 induced α-to-β cell conversion as assessed by the presence of YFP reporter in new β-cells. In addition, these Pax4-treated islets increased glucose-stimulated insulin secretion compare to control group. Furthermore, we transplanted Pax4-treated primary mouse islets into kidney capsule of the streptozotocin-induced diabetic mice and found that they significantly reduced the blood glucose and improved glucose tolerance compared to control groups. These data indicate that Pax4 induced α- to functional β-cell conversion, and proved therapeutic benefits for islet transplantation. Disclosure K.R. Parajuli: None. Y. Zhang: None. H. Wu: None.