Vascular Endothelial Growth Factor Increases Functional β-Cell Mass by Improvement of Angiogenesis of Isolated Human and Murine Pancreatic Islets

Lai, Yi; Schneider, Darius; Kidszun, André; Hauck‐Schmalenberger, Ingrid; Breier, Georg; Brandhorst, Daniel; Brandhorst, Heide; Iken, Marcus; Brendel, Mathias D.; Bretzel, Reinhard G.; Linn, Thomas

doi:10.1097/01.tp.0000163506.40189.65

Cited by 141 publications

(122 citation statements)

References 20 publications

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“…We have shown that normal isolated human islets express the VEGF receptors VEGF-R1, -R2 and -R3, as well as the coreceptor neuropilin 1. We have reproduced the recently described data on VEGF production in isolated human islets [35], yet our data suggest that VEGF is produced under standard culture conditions, in contrast to the hypoxic environment used in the study by Lai et al [35]. The expression of neuropilin 1 has previously been described in islet cells using immunohistochemistry of pancreas sections from chronic pancreatitis specimens [36].…”

Section: Discussionsupporting

confidence: 84%

Vascular endothelial growth factor as a survival factor for human islets: effect of immunosuppressive drugs

et al. 2007

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Aims/hypothesis Rapamycin, part of the immunosuppressive regimen of the Edmonton protocol, has been shown to inhibit vascular endothelial growth factor (VEGF) production and VEGF-mediated survival signalling in tumour cell lines. This study investigates the survival-promoting activities of VEGF in human islets and the effects of rapamycin on islet viability.Materials and methods Levels of VEGF and its receptors in isolated human islets and whole pancreas was determined by western blotting and immunostaining. Islet viability following VEGF or immunosuppressive drug treatment was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Islet VEGF release was measured by ELISA. Mouse islets infected with an adenovirus expressing the gene for VEGF were transplanted syngeneically into streptozotocin-induced diabetic mice, with blood glucose levels measured three times per week. Results Isolated human islets produced multiple isoforms of VEGF and VEGF receptors 1, 2 and 3 and the coreceptor neuropilin 1. Exogenous VEGF (10 ng/ml) prevented human islet death induced by serum starvation, which suggests that VEGF can act as a survival factor for human islets. Transplantation of mouse islets infected with a VEGF-expressing adenovirus in a syngeneic model, improved glycaemic control at day 1 post-transplantation (p< 0.05). Rapamycin at 10 and 100 ng/ml significantly reduced islet VEGF release (by 37±4% and 43±6%, respectively; p<0.05) and at 100 ng/ml reduced islet viability (by 36±9%) and insulin release (by 47±7%, all vs vehicle-treated controls; p<0.05). Tacrolimus had no effect on islet VEGF release or viability. Conclusions/interpretation Our data suggest that rapamycin may have deleterious effects on islet survival posttransplantation, both through a direct effect on islet viability and indirectly through blockade of VEGF-mediated revascularisation.

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Section: Discussionsupporting

confidence: 84%

Vascular endothelial growth factor as a survival factor for human islets: effect of immunosuppressive drugs

et al. 2007

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“…50 Several studies have previously demonstrated improved islet graft revascularization in response to the production of recombinant VEGF-A within the islets. 8,9 However, unlike other pretreatment procedures for introducing VEGF-A to the islets, such as gene therapy, 8,9,51 anchoring VEGF-A directly to immobilized heparin on the islet surface should not be associated with an increased risk of inducing adverse effects on islet function 52,53 or adaptive immune responses. Importantly, islet functionality was not affected by anchoring of VEGF-A in this study because the growth factor in combination with immobilized heparin did not affect insulin release in response to a glucose challenge.…”

Section: Figmentioning

confidence: 99%

“…[4][5][6] Growth factors, particularly vascular endothelial growth factor (VEGF), are known to contribute significantly to the vascularization of transplanted islets. [7][8][9][10][11] The VEGF family of homodimeric glycoproteins in humans consists of VEGF-A, -B, -C, -D and placental growth factor. VEGF-A is critical during development as shown by lethality of transgenic mice lacking one allele.…”

Section: Introductionmentioning

confidence: 99%

Anchoring of Vascular Endothelial Growth Factor to Surface-Immobilized Heparin on Pancreatic Islets: Implications for Stimulating Islet Angiogenesis

Cabric

Sánchez

Johansson

et al. 2010

Tissue Engineering Part A

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“…Several biological factors such as glucagon-like peptide-1, 53 VEGF, 27,[103][104][105][106] and hepatocyte growth factor/scatter 107,108 can be used to stimulate islet function. Other factors can also be used to create a more-conducive environment for transplantation.…”

Section: Additional Strategies To Increase Islet Cell Survival and Fumentioning

confidence: 99%

Islet Encapsulation: Strategies to Enhance Islet Cell Functions

et al. 2007

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Diabetes is one of the most prevalent, costly, and debilitating diseases in the world. Although traditional insulin therapy has alleviated the short-term effects, long-term complications are ubiquitous and harmful. For these reasons, alternative treatment options are being developed. This review investigates one appealing area: cell replacement using encapsulated islets. Encapsulation materials, encapsulation methods, and cell sources are presented and discussed. In addition, the major factors that currently limit cell viability and functionality are reviewed, and strategies to overcome these limitations are examined. This review is designed to introduce the reader to cell replacement therapy and cell and tissue encapsulation, especially as it applies to diabetes.

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Vascular Endothelial Growth Factor Increases Functional β-Cell Mass by Improvement of Angiogenesis of Isolated Human and Murine Pancreatic Islets

Abstract: Optimized angiogenesis of islet transplants resulted in greater availability of insulin caused by beta-cell proliferation and a significantly higher percentage (90% versus 20%) of mice cured from diabetes.

Cited by 141 publications

References 20 publications

Vascular endothelial growth factor as a survival factor for human islets: effect of immunosuppressive drugs

Vascular endothelial growth factor as a survival factor for human islets: effect of immunosuppressive drugs

Anchoring of Vascular Endothelial Growth Factor to Surface-Immobilized Heparin on Pancreatic Islets: Implications for Stimulating Islet Angiogenesis

Islet Encapsulation: Strategies to Enhance Islet Cell Functions

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