Improved vascular engraftment and graft function after inhibition of the angiostatic factor thrombospondin-1 in mouse pancreatic islets
Improved vascular engraftment and graft function after inhibition of the angiostatic factor thrombospondin-1 in mouse pancreatic islets
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DOI：
10.2337/db07-0724
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发表时间：
2008-07-01
期刊：
影响因子：
7.7
通讯作者：
Carlsson, Per-Ola
中科院分区：
文献类型：
--
作者：
Olerud, Johan;Johansson, Magnus;Carlsson, Per-Ola
目的：移植后新的胰岛内毛细血管网络发育不足可能是导致临床胰岛移植失败的原因之一。本研究验证了通常存在于胰岛的血管抑制因子血小板反应蛋白-1 （TSP-1）在移植后限制胰岛内血管扩张的假设。研究设计和方法：将TSP-1缺陷（-/-）小鼠的胰岛或转染了TSP-1 siRNA的野生型胰岛移植到同基因或免疫功能低下的受体小鼠的肾包膜下。结果：移植后1个月，与对照胰岛细胞相比，遗传上TSP-1（-/-）胰岛细胞和TSP-1 sirna转染的胰岛细胞血管密度均增加。这也反映在移植物的血液预融合和氧合明显增加。通过比较胰岛细胞在植入前转染TSP-1 siRNA或scramble siRNA时葡萄糖刺激胰岛素释放的情况，分析改善血管植入的功能重要性。这些实验表明，由TSP-1 sirna转染的胰岛细胞组成的移植物血运重建的增加与第一和第二阶段葡萄糖刺激的胰岛素分泌的增加有关。结论：我们的研究结果表明，抑制胰岛移植胰岛的TSP-1可能是改善胰岛移植物血运重建和功能的可行策略。
OBJECTIVE-Insufficient development of a new intra-islet capillary network after transplantation may be one contributing factor to the failure of islet grafts in clinical transplantation. The present study tested the hypothesis that the angiostatic factor thrombospondin-1 (TSP-1), which is normally present in islets, restricts intra-islet vascular expansion posttransplantation.RESEARCH DESIGN AND METHODS-Pancreatic islets of TSP-1-deficient (TSP-1(-/-)) mice or wild-type islets transfected with siRNA for TSP-1 were transplanted beneath the renal capsule of syngeneic or immunocompromised recipient mice.RESULTS-Both genetically TSP-1(-/-) islets and TSP-1 siRNA-transfected islet cells demonstrated an increased vascular density when compared with control islets I month after transplantation. This was also reflected in a markedly increased blood per-fusion and oxygenation of the grafts. The functional importance of the improved vascular engraftment was analyzed by comparing glucose-stimulated insulin release from islet cells transfected with either TSP-1 siRNA or scramble siRNA before implantation. These experiments showed that the increased revascularization of grafts composed of TSP-1 siRNA-transfected islet cells correlated to increments in both their first and second phase of glucose-stimulated insulin secretion.CONCLUSIONS-Our findings demonstrate that inhibition of TSP-1 in islets intended for transplantation may be a feasible strategy to improve islet graft revascularization and function.