کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1426042 | 1509081 | 2009 | 6 صفحه PDF | دانلود رایگان |
Islet transplantation has great potential as an effective means of treating type 1 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 β-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-α, IL-1β and IFN-γ. 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.
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Journal: Journal of Controlled Release - Volume 140, Issue 3, 16 December 2009, Pages 262–267