title: PAX4 Gene Transfer Induces α-to-β Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment.
abstract: The transcription factor Pax4 plays a critical role in the determination of α- versus β-cell lineage during endocrine pancreas development. In this study, we explored whether Pax4 gene transfer into α-cells could convert them into functional β-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 αTC1.9 cells. More importantly, these cells exhibited glucose-stimulated insulin secretion, a key feature of functional β-cells. When injected into streptozotocin-induced diabetic mice, Pax4-treated αTC1.9 cells significantly reduced blood glucose, and the mice showed better glucose tolerance, supporting that Pax4 gene transfer into αTC1.9 cells resulted in the formation of functional β-cells. Furthermore, treatment of primary human islets with Ad5.Pax4 resulted in significantly improved β-cell function. Detection of glucagon(+)/Pax4(+)/Insulin(+) cells argued for Pax4-induced α-to-β 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.
authors.affiliation: Section of Endocrinology, Department of Medicine, Tulane University Health Science Center, New Orleans, Louisiana, USA.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Section of Endocrinology, Department of Medicine, Tulane University Health Science Center, New Orleans, Louisiana, USA.
authors.forename: Genevieve E
authors.initials: GE
authors.lastname: Fava
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Section of Endocrinology, Department of Medicine, Tulane University Health Science Center, New Orleans, Louisiana, USA.
authors.forename: Franck
authors.initials: F
authors.lastname: Mauvais-Jarvis
authors.affiliation: Section of Endocrinology, Department of Medicine, Tulane University Health Science Center, New Orleans, Louisiana, USA.
authors.forename: Vivian A
authors.initials: VA
authors.lastname: Fonseca
authors.affiliation: Section of Endocrinology, Department of Medicine, Tulane University Health Science Center, New Orleans, Louisiana, USA. Electronic address: hwu3@tulane.edu.
authors.forename: Hongju
authors.initials: H
authors.lastname: Wu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D005934:Glucagon / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000473:pathology; D051379:Mice; D051761:Paired Box Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; C491709:PAX4 protein, human; D051761:Paired Box Transcription Factors; D005934:Glucagon