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

¹Rangos Research Center, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
²Department of Gene & Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029

Correspondence: dongh{at}pitt.edu

Key Words: Islet Transplantation • Islet Engraftment • Angiopoietin-1 • Cytokine • Type 1 Diabetes • Mice

Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, but only a small fraction of implanted islets becomes engrafted. The underlying mechanisms remain elusive. To probe the mechanism of islet revascularization, we determined the effect of Ang-1, a pro-angiogenic and anti-apoptotic 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 that were pre-transduced with Ang-1 vector exhibited near normoglycemia post-transplantation. In contrast, diabetic mice receiving an equivalent islet mass pre-transduced with control vector remained hyperglycemic. 30 days post transplantation, mice were sacrificed and islet grafts were 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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