Gene expression and silencing for improved islet transplantation

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)262-267
Number of pages6
JournalJournal of Controlled Release
Volume140
Issue number3
DOIs
StatePublished - Dec 16 2009

Keywords

  • Adenoviral vectors
  • Caspase-3
  • Hepatocyte growth factor
  • Human islets
  • IL-1Ra
  • Islet transplantation
  • hVEGF
  • siRNA

ASJC Scopus subject areas

  • Pharmaceutical Science

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