Angiopoietin-1 Production in Islets Improves Islet Engraftment and Protects Islets From Cytokine-Induced Apoptosis
Dongming Su 1 ,
Nan Zhang 2 ,
Jing He 1 ,
Shen Qu 1 ,
Sandra Slusher 1 ,
Rita Bottino 1 ,
Suzanne Bertera 1 ,
Jonathan Bromberg 2 and
H. Henry Dong 1
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
Abstract
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.
Ang-1, angiopoietin-1
IFN-γ, γ-interferon
IL, interleukin
MOI, multiplicity of infection
TNF, tumor necrosis factor
VEGF, vascular endothelial growth factor
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 26 June 2007. DOI: 10.2337/db07-0371.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted June 19, 2007.
Received March 16, 2007.
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Angiopoietin-1 Production in Islets Improves Islet Engraftment and Protects Islets From Cytokine-Induced Apoptosis

10.2337/db07-0371