Gene expression and silencing for improved islet transplantation

JOURNAL OF CONTROLLED RELEASE

卷:140

Article; Proceedings Paper

Mahato, Ram I.

关键词: Human islets;    Adenoviral vectors;    hVEGF;    IL-1Ra;    Hepatocyte growth factor;    Caspase-3;    siRNA;    Islet transplantation;   

DOI  :  10.1016/j.jconrel.2009.04.011

来源: Elsevier

【 摘 要 】

Islet transplantation has great potential as an effective means of treating type l diabetes. However, its successful application greatly depends on the rapid revascularization of islets and prevention from their apoptotic cell death. We co-expressed human vascular endothelial growth factor (hVEGF) and human interleukin-1 receptor antagonist (hIL-1Ra) after transduction of human islets with Adv-hVEGF-hIL-1Ra. Since hepatocyte growth factor (HGF) increases beta-cell proliferation and promotes revascularization of islets, we also constructed Adv-hHGF-hIL-1Ra There was dose and time dependent expression of hVEGF and hIL-1Ra or hHGF and hIL-1Ra by islets, which led to decrease in caspase-3 activity and apoptosis induced by a cocktail of TNF-alpha, IL-1 beta and IFN-gamma. Compared to non-treated islets, transduction of islets with these bipartite Adv vectors prior to transplantation under the kidney capsules of diabetic NOD-SCID mice reduced the blood glucose levels, and increased serum insulin and c-peptide levels. Immunohistochemical staining of the islet bearing kidney sections was positive for human insulin, growth factor (hVEGF or hHGF) and von Willebrand factor. Transduction with Adv-caspase-3-shRNA also prevented islets from cytokine induced apoptosis and improved islet transplantation. In conclusion, bipartite Adv vector efficiently co-expressed both growth factor and antiapoptotic genes or shRNA targeting pro-apoptotic genes, decreases apoptosis and improves the outcome of islet transplantation. (C) 2009 Elsevier B.V. All rights reserved.

【 授权许可】

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