Centre Européen d'étude du Diabète, Strasbourg, France.
Cell Transplant. 2011;20(9):1333-42. doi: 10.3727/096368910X557182. Epub 2011 Feb 3.
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.
胰岛移植过程中血管重建延迟和不足会导致胰岛缺氧和营养物质缺乏，从而导致移植物功能衰竭。血管内皮生长因子（VEGF）在胰岛血管重建中可能发挥关键作用。我们旨在开发使用铁螯合剂去铁胺（DFO）在胰岛中过表达 VEGF 的药理学策略，从而避免与基因治疗相关的障碍或安全风险。使用编码人 VEGF 基因的腺病毒（ADE）（4.10(8) pfu/胰腺）体内感染大鼠胰岛，或在存在 DFO（10 μmol/L）的情况下孵育胰岛。在治疗后 1 和 3 天评估胰岛的体外活力、功能和 VEGF 的分泌。将感染的胰岛或用 DFO 孵育的胰岛移植到同基因糖尿病大鼠的肝脏中，并通过测量体重、血糖、C 肽分泌和动物存活来估计体内移植物效率在 2 个月的过程中。DFO 在 3 天内诱导短暂的 VEGF 过表达，而 ADE 感染导致持续 14 天的 VEGF 过表达；然而，这是有毒的，降低了胰岛的活力和功能。体内研究表明，与假手术和对照组相比，用 DFO 或 ADE 处理的胰岛移植后大鼠死亡率降低。ADE 治疗改善了体重和 C 肽水平。基因治疗和 DFO 改善了移植后糖尿病大鼠的代谢控制，但在 DFO 存在的情况下，这种效果是有限的。药物治疗是一种提高移植过程中移植物效率的有趣策略，但这种方法需要用更具特异性的药物进行改进。
