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Angiopoietin-1 Production in Islets Improves Islet Engraftment and Protects Islets From Cytokine-Induced Apoptosis

¹ Department of Pediatrics, Rangos Research Center, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
² Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York

Address correspondence and reprint requests to Dr. Henry Dong, Rangos Research Center, Children's Hospital of Pittsburgh, 3460 5th Ave., Rm. 5140, Pittsburgh, PA 15213. E-mail: dongh{at}pitt.edu

Abbreviations: Ang-1, angiopoietin-1; IFN-, -interferon; IL, interleukin; MOI, multiplicity of infection; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor

Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, but only a small fraction of implanted islets become engrafted. The underlying mechanisms remain elusive. To probe the mechanism of islet revascularization, we determined the effect of angiopoietin-1 (Ang-1), a proangiogenic and antiapoptotic factor, on the survival, function, and revascularization of transplanted islets using a syngeneic model. Islets were transduced with adenoviruses expressing Ang-1 or control LacZ, followed by transplantation under the renal capsule. Diabetic mice receiving a marginal mass of 150 islets pretransduced with Ang-1 vector exhibited near normoglycemia posttransplantation. In contrast, diabetic mice receiving an equivalent islet mass pretransduced with control vector remained hyperglycemic. At 30 days posttransplantation, mice were killed and islet grafts retrieved for immunohistochemistry. Islet grafts with elevated Ang-1 production retained significantly increased microvascular density, improved glucose profiles, and increased glucose-stimulated insulin release. Cultured islets expressing Ang-1 displayed improved viability and enhanced glucose-stimulated insulin secretion in the presence of cytokines. In contrast, control islets exhibited increased apoptosis and diminished glucose-stimulated insulin release in response to cytokine treatment. These results indicate that Ang-1 confers a cytoprotective effect on islets, enhancing islet engraftment and preserving functional islet mass in transplants.

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