Influence of VEGF on the Viability of Encapsulated Pancreatic Rat Islets after Transplantation in Diabetic Mice

Abstract

After pancreatic islet transplantation, insufficient blood supply is responsible for the loss of islet viability. The aim of our study was: 1) to determine the influence of vascular endothelial growth factor (VEGF) on the survival of encapsulated rat islets transplanted into healthy and diabetic mice and 2) to evaluate the metabolic efficiency of the VEGF-supplemented grafts. Twenty-four hours after culture, 50 rat islets immobilized into collagen in the presence of VEGF (100 ng/ml) and encapsulated (AN69 membrane, HOSPAL) were grafted in the peritoneal cavity of healthy or streptozotocin-induced diabetic mice (n = 6). Seven, 14, and 28 days after implantation, the encapsulation device and tissue surrounding the device were removed and the following parameters were analyzed: the number and the diameter of buds, the distance between devices and buds, the amount of cellular adhesion on the capsule surface, and the level of insulin secreted by encapsulated islet. For reversal of diabetes, 1000 rat islets encapsulated in the presence of VEGF were implanted in the peritoneal cavity of diabetic mice and fasting glycemia was analyzed. After 7 days of islet implantation in the absence of VEGF, the bud diameter was 16.1 ± 6.9 µm in diabetic mice and 34.4 ± 3.9 µm in healthy mice. However, the number of buds increased by a factor 2.5 in the presence of VEGF in both types of mice. Furthermore, when islets were transplanted in the presence of VEGF, the distance between the device and the buds was significantly decreased in both types of mice (p < 0.001) after 7, 14, and 28 days of islet implantation. Capsule analysis showed a decrease in cellular adhesion when the islets were encapsulated in the presence of VEGF. Insulin secretion of the islets was higher in the presence of VEGF compared with islets alone at all steps of the study. When 1000 rat islets were transplanted in the presence of VEGF, the glycemia level decreased to 6.2 ± 0.8 mmol/L after 3 days and remained stable until at least 28 days. In contrast, in the absence of VEGF, the initial decrease in the glucose level was rapidly followed by a relapse in hyperglycemia. In summary, VEGF increased the viability of engrafted encapsulated islets, increasing the duration of a normalized glycemia in diabetic mice following transplantation. Local adjunction of VEGF may therefore improve the clinical outcome of islet transplantation.

Fibrin supports human fetal islet-epithelial cell differentiation via p70s6k and promotes vascular formation during transplantation

“…48 Likewise, normalization of glycemia occurred when fibrin-encapsulated VEGF-treated rat islets were transplanted into diabetic mice. 49 Results from these studies in combination with our own confirm that blood vessel formation is important for the maintenance of islet graft function and survival.…”

Elevated Vascular Endothelial Growth Factor Production in Islets Improves Islet Graft Vascularization

“…Using a different approach by which murine islets were immobilized with collagen in the presence of VEGF protein and encapsulated before transplantation into the peritoneal cavity, Sigrist et al (37) showed that local release of VEGF within the grafts significantly increased the viability of transplanted islets, resulting in extended physiological control of glycemia in STZ-induced diabetic mice. Although therapeutic angiogenesis has been used for treating coronary and peripheral artery diseases by facilitating new vessel formation using plasmid or adenoviral vector-mediated VEGF gene delivery in a number of clinical trials (38 -44), our present results together with others suggest that a similar strategy should be explored to allow local production/release of angiogenic molecules in islet grafts to accelerate islet revascularization.…”

Biological and Biomaterial Approaches for Improved Islet Transplantation

“…Achievement of rapid revascularization is expected to improve the viability and functioning of transplanted islets. This may be achieved by ex vivo VEGF gene delivery to islets (Narang et al, 2004) or by coencapsulating VEGF protein with islets during microencapsulation (Sigrist et al, 2003a). These approaches are discussed in section V.…”