RGD peptide-modified adenovirus expressing hepatocyte growth factor and X-linked inhibitor of apoptosis improves islet transplantation

Hao Wu, A. Rum Yoon, Feng Li, Chae Ok Yun, Ram I. Mahato

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: Islet transplantation has the potential for treating type I diabetes; however, its widespread clinical application is limited by the massive apoptotic cell death and poor revascularization of transplanted islet grafts. Methods: We constructed a surface-modified adenoviral vector with RGD (Arg-Gly-Asp) sequences encoding human X-linked inhibitor of apoptosis and hepatocyte growth factor (RGD-Adv-hHGF-hXIAP). In vitro transgene expression in human islets was determined by enzyme-liniked immunosorbent assay. RGD-Adv-hHGF-hXIAP-transduced human islets were transplanted under the kidney capsule of streptozotocin-induced diabetic NOD/SCID mice. The blood glucose levels of mice were measured weekly. The kidneys bearing islets were isolated at the end of the experiment and subjected to immunofluorescence staining. Results: The transduction efficiency on human islets was significantly improved using RGD-modified adenovirus. HGF and XIAP gene expressions were dose-dependent after viral transduction. When exposed to a cocktail of inflammatory cytokines, RGD-Adv-hHGF-hXIAP-transduced human islets showed decreased caspase 3 activity and reduced apoptotic cell death. Prolonged normoglycemic control could be achieved by transplanting RGD-Adv-hHGF-hXIAP-transduced human islets. Immunofluorescence staining of kidney sections bearing RGD-Adv-hHGF-hXIAP-transduced islets was positive for insulin and von Willebrand factor (vWF) at 200days after transplantation. Conclusions: These results indicated that ex vivo transduction of islets with RGD-Adv-hHGF-hXIAP decreased apoptotic islet cell death and improved islet revascularization, and eventually might improve the outcome of human islet transplantation.

Original languageEnglish (US)
Pages (from-to)658-669
Number of pages12
JournalJournal of Gene Medicine
Volume13
Issue number12
DOIs
StatePublished - Dec 1 2011

Fingerprint

Factor X
Islets of Langerhans Transplantation
Hepatocyte Growth Factor
Adenoviridae
Apoptosis
Cell Death
Kidney
Fluorescent Antibody Technique
Staining and Labeling
Immunosorbents
Inbred NOD Mouse
SCID Mice
von Willebrand Factor
Streptozocin
arginyl-glycyl-aspartic acid
Type 1 Diabetes Mellitus
Transgenes
Islets of Langerhans
Caspase 3
Capsules

Keywords

  • Adenovirus
  • Apoptosis
  • Islets
  • RGD
  • Revascularization

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Drug Discovery
  • Genetics(clinical)

Cite this

RGD peptide-modified adenovirus expressing hepatocyte growth factor and X-linked inhibitor of apoptosis improves islet transplantation. / Wu, Hao; Yoon, A. Rum; Li, Feng; Yun, Chae Ok; Mahato, Ram I.

In: Journal of Gene Medicine, Vol. 13, No. 12, 01.12.2011, p. 658-669.

Research output: Contribution to journalArticle

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abstract = "Background: Islet transplantation has the potential for treating type I diabetes; however, its widespread clinical application is limited by the massive apoptotic cell death and poor revascularization of transplanted islet grafts. Methods: We constructed a surface-modified adenoviral vector with RGD (Arg-Gly-Asp) sequences encoding human X-linked inhibitor of apoptosis and hepatocyte growth factor (RGD-Adv-hHGF-hXIAP). In vitro transgene expression in human islets was determined by enzyme-liniked immunosorbent assay. RGD-Adv-hHGF-hXIAP-transduced human islets were transplanted under the kidney capsule of streptozotocin-induced diabetic NOD/SCID mice. The blood glucose levels of mice were measured weekly. The kidneys bearing islets were isolated at the end of the experiment and subjected to immunofluorescence staining. Results: The transduction efficiency on human islets was significantly improved using RGD-modified adenovirus. HGF and XIAP gene expressions were dose-dependent after viral transduction. When exposed to a cocktail of inflammatory cytokines, RGD-Adv-hHGF-hXIAP-transduced human islets showed decreased caspase 3 activity and reduced apoptotic cell death. Prolonged normoglycemic control could be achieved by transplanting RGD-Adv-hHGF-hXIAP-transduced human islets. Immunofluorescence staining of kidney sections bearing RGD-Adv-hHGF-hXIAP-transduced islets was positive for insulin and von Willebrand factor (vWF) at 200days after transplantation. Conclusions: These results indicated that ex vivo transduction of islets with RGD-Adv-hHGF-hXIAP decreased apoptotic islet cell death and improved islet revascularization, and eventually might improve the outcome of human islet transplantation.",
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AU - Yoon, A. Rum

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AU - Yun, Chae Ok

AU - Mahato, Ram I.

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N2 - Background: Islet transplantation has the potential for treating type I diabetes; however, its widespread clinical application is limited by the massive apoptotic cell death and poor revascularization of transplanted islet grafts. Methods: We constructed a surface-modified adenoviral vector with RGD (Arg-Gly-Asp) sequences encoding human X-linked inhibitor of apoptosis and hepatocyte growth factor (RGD-Adv-hHGF-hXIAP). In vitro transgene expression in human islets was determined by enzyme-liniked immunosorbent assay. RGD-Adv-hHGF-hXIAP-transduced human islets were transplanted under the kidney capsule of streptozotocin-induced diabetic NOD/SCID mice. The blood glucose levels of mice were measured weekly. The kidneys bearing islets were isolated at the end of the experiment and subjected to immunofluorescence staining. Results: The transduction efficiency on human islets was significantly improved using RGD-modified adenovirus. HGF and XIAP gene expressions were dose-dependent after viral transduction. When exposed to a cocktail of inflammatory cytokines, RGD-Adv-hHGF-hXIAP-transduced human islets showed decreased caspase 3 activity and reduced apoptotic cell death. Prolonged normoglycemic control could be achieved by transplanting RGD-Adv-hHGF-hXIAP-transduced human islets. Immunofluorescence staining of kidney sections bearing RGD-Adv-hHGF-hXIAP-transduced islets was positive for insulin and von Willebrand factor (vWF) at 200days after transplantation. Conclusions: These results indicated that ex vivo transduction of islets with RGD-Adv-hHGF-hXIAP decreased apoptotic islet cell death and improved islet revascularization, and eventually might improve the outcome of human islet transplantation.

AB - Background: Islet transplantation has the potential for treating type I diabetes; however, its widespread clinical application is limited by the massive apoptotic cell death and poor revascularization of transplanted islet grafts. Methods: We constructed a surface-modified adenoviral vector with RGD (Arg-Gly-Asp) sequences encoding human X-linked inhibitor of apoptosis and hepatocyte growth factor (RGD-Adv-hHGF-hXIAP). In vitro transgene expression in human islets was determined by enzyme-liniked immunosorbent assay. RGD-Adv-hHGF-hXIAP-transduced human islets were transplanted under the kidney capsule of streptozotocin-induced diabetic NOD/SCID mice. The blood glucose levels of mice were measured weekly. The kidneys bearing islets were isolated at the end of the experiment and subjected to immunofluorescence staining. Results: The transduction efficiency on human islets was significantly improved using RGD-modified adenovirus. HGF and XIAP gene expressions were dose-dependent after viral transduction. When exposed to a cocktail of inflammatory cytokines, RGD-Adv-hHGF-hXIAP-transduced human islets showed decreased caspase 3 activity and reduced apoptotic cell death. Prolonged normoglycemic control could be achieved by transplanting RGD-Adv-hHGF-hXIAP-transduced human islets. Immunofluorescence staining of kidney sections bearing RGD-Adv-hHGF-hXIAP-transduced islets was positive for insulin and von Willebrand factor (vWF) at 200days after transplantation. Conclusions: These results indicated that ex vivo transduction of islets with RGD-Adv-hHGF-hXIAP decreased apoptotic islet cell death and improved islet revascularization, and eventually might improve the outcome of human islet transplantation.

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