Influence of VEGF on the viability of encapsulated pancreatic rat islets after transplantation in diabetic mice.
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 microm in diabetic mice and 34.4 +/- 3.9 microm 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.
Centre européen d'étude du Diabète, Faculté de Médecine, 11, rue Humann, 67 000, Strasbourg, France.
S
S
Sigrist
A
A
Mechine-Neuville
K
K
Mandes
V
V
Calenda
S
S
Braun
G
G
Legeay
J P
JP
Bellocq
M
M
Pinget
L
L
Kessler
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D004195:Disease Models, Animal; D006085:Graft Survival / Q000187:drug effects* / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D051379:Mice; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D010537:Peritoneum / Q000166:cytology / Q000502:physiology / Q000601:surgery; D051381:Rats; D014183:Transplantation, Heterologous / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology* / Q000627:therapeutic use
D001786:Blood Glucose; D007328:Insulin; D042461:Vascular Endothelial Growth Factor A