Elevation of Vascular Endothelial Growth Factor Production and Its Effect on Revascularization and Function of Graft Islets in Diabetic Rats

Cheng, Ying; Liu, Y.; Zhang, J.; Li, T.; Zhao, Ning

doi:10.1097/00007890-201007272-01957

Cited by 3 publications

(3 citation statements)

References 3 publications

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“…This study confirmed the key role of VEGF in the improvement of islet engraftment efficiency (3,46,53). Several authors have thus focused on developing strategies to overexpress VEGF in pancreatic islets using viral infection (6,7). However, VEGF is efficiently overexpressed by adenoviral infection (6,12), but there are several obstacles or safety risks associated with gene therapy, such as the transduction of unwanted cells, which is particularly relevant here, thus requiring fine-tuned transgene expression.…”

Section: Discussionmentioning

confidence: 99%

Improvement of Rat Islet Viability during Transplantation: Validation of Pharmacological Approach to Induce VEGF Overexpression

Langlois¹,

Bietiger²,

Seyfritz³

et al. 2011

Cell Transplant

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Delayed and insufficient revascularization during islet transplantation deprives islets of oxygen and nutrients, resulting in graft failure. Vascular endothelial growth factor (VEGF) could play a critical role in islet revascularization. We aimed to develop pharmacological strategies for VEGF overexpression in pancreatic islets using the iron chelator deferoxamine (DFO), thus avoiding obstacles or safety risks associated with gene therapy. Rat pancreatic islets were infected in vivo using an adenovirus (ADE) encoding human VEGF gene (4.10(8) pfu/pancreas) or were incubated in the presence of DFO (10 μmol/L). In vitro viability, functionality, and the secretion of VEGF were evaluated in islets 1 and 3 days after treatment. Infected islets or islets incubated with DFO were transplanted into the liver of syngenic diabetic rats and the graft efficiency was estimated in vivo by measuring body weight, glycemia, C-peptide secretion, and animal survival over a period of 2 months. DFO induced transient VEGF overexpression over 3 days, whereas infection with ADE resulted in prolonged VEGF overexpression lasting 14 days; however, this was toxic and decreased islet viability and functionality. The in vivo study showed a decrease in rat deaths after the transplantation of islets treated with DFO or ADE compared with the sham and control group. ADE treatment improved body weight and C-peptide levels. Gene therapy and DFO improved metabolic control in diabetic rats after transplantation, but this effect was limited in the presence of DFO. The pharmacological approach is an interesting strategy for improving graft efficiency during transplantation, but this approach needs to be improved with drugs that are more specific.

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Section: Discussionmentioning

confidence: 99%

Improvement of Rat Islet Viability during Transplantation: Validation of Pharmacological Approach to Induce VEGF Overexpression

Langlois¹,

Bietiger²,

Seyfritz³

et al. 2011

Cell Transplant

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“…In conclusion, our results indicate that regulated overexpression of hVEGF in a hypoxia-inducible manner enhances islet vascular engraftment and preserves islet function overtime in transplants. transfer strategies have been investigated [10][11][12][13][14][15][16][17][18]. Among the angiogenic genes, delivery of vascular endothelial growth factor (VEGF) to islets using adenoviral vectors or nonviral carriers [13][14][15][16][17][18] has been shown to increase the survival of transplanted islets.…”

Section: Discussionmentioning

confidence: 99%

Effect of hypoxia-inducible VEGF gene expression on revascularization and graft function in mouse islet transplantation

Lee¹,

Lee²,

Chae³

et al. 2010

Transplant International

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Summary For gene transfer strategies to improve islet engraftment, vascular endothelial growth factor (VEGF) expression should be regulated in a way that matches the transient nature of revascularization with simultaneously avoiding undesirable effects of overexpression. The aim of this study was to investigate the effects of hypoxia‐inducible VEGF gene transfer using the RTP801 promoter on islet grafts. We implanted pSV‐hVEGF transfected, pRTP801‐hVEGF transfected or nontransfected mouse islets under the kidney capsule of streptozotocin‐induced diabetic syngeneic mice. Human VEGF immunostaining of day 3 grafts revealed that the pRTP801‐hVEGF transfected group had higher hVEGF expression compared with the pSV‐hVEGF transfected group. BS‐1 staining of day 3 grafts from the pRTP801‐hVEGF transfected group showed the highest vascular density, which was comparable with day 6 grafts from the nontransfected group. In 360 islet equivalent (IEQ)‐transplantation which reverted hyperglycemia in all mice, the area under the curve of glucose levels during intraperitoneal glucose tolerance test 7 weeks post‐transplant was lower in mice transplanted with pRTP801‐hVEGF transfected grafts compared with mice transplanted with nontransfected grafts. In 220 IEQ‐transplantations, diabetic mice transplanted with pRTP801‐hVEGF islets became normoglycemic more rapidly compared with mice transplanted with pSV‐hVEGF or nontransfected islets, and diabetes reversal rate after 50 days was 90%, 68%, and 50%, respectively. In conclusion, our results indicate that regulated overexpression of hVEGF in a hypoxia‐inducible manner enhances islet vascular engraftment and preserves islet function overtime in transplants.

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“…Moreover, recently it has been reported that in animal models MSCs are able to enhance survival and function of islet graft not only by immune modulation mechanisms (5) but also by increasing islet revascularization (20). In detail, MSCs secrete cytokines like vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), which are able both to protect endocrine and endothelial islet cells after isolation and to increase islet revascularization after transplant (8, 11, 14, 33).…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cells and Islet Cotransplantation in Diabetic Rats: Improved Islet Graft Revascularization and Function by Human Adipose Tissue-Derived Stem Cells Preconditioned with Natural Molecules

et al. 2012

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Hypoxia plays an important role in limiting the engraftment, survival, and function of intrahepatically transplanted islets. Mesenchymal stem cells (MSCs) were recently used in animal models of islet transplantation not only to reduce allograft rejection but also to promote revascularization. Among different possible origins, adipose tissue represents a novel and good source of MSCs. Moreover, the capability of adipose tissue-derived stem cells (ASCs) to improve islet graft revascularization was recently reported after hybrid transplantation in mice. Within this context, we have previously shown that hyaluronan esters of butyric and retinoic acids can significantly enhance the rescuing potential of human MSCs (hMSCs). Here we evaluated whether ex vivo preconditioning of human ASCs (hASCs) with a mixture of hyaluronic (HA), butyric (BU), and retinoic (RA) acids may result in optimization of graft revascularization after islet/stem cell intrahepatic cotransplantation in syngeneic diabetic rats. We demonstrated that hASCs exposed to the mixture of molecules are able to increase the secretion of vascular endothelial growth factor (VEGF) as well as the transcription of angiogenic genes, including VEGF, KDR (kinase insert domain receptor), and hepatocyte growth factor (HGF). Rats transplanted with islets cocultured with preconditioned hASCs exhibited a better glycemic control than rats transplanted with an equal volume of islets and control hASCs. Cotransplantation with preconditioned hASCs was also associated with enhanced islet revascularization in vivo, as highlighted by graft morphological analysis. The observed increase in islet graft revascularization and function suggests that our method of stem cell preconditioning may represent a novel strategy to remarkably improve the efficacy of islets-hMSCs cotransplantation.

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Elevation of Vascular Endothelial Growth Factor Production and Its Effect on Revascularization and Function of Graft Islets in Diabetic Rats

Cited by 3 publications

References 3 publications

Improvement of Rat Islet Viability during Transplantation: Validation of Pharmacological Approach to Induce VEGF Overexpression

Improvement of Rat Islet Viability during Transplantation: Validation of Pharmacological Approach to Induce VEGF Overexpression

Effect of hypoxia-inducible VEGF gene expression on revascularization and graft function in mouse islet transplantation

Mesenchymal Stem Cells and Islet Cotransplantation in Diabetic Rats: Improved Islet Graft Revascularization and Function by Human Adipose Tissue-Derived Stem Cells Preconditioned with Natural Molecules

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