Microvesicles Derived From Endothelial Progenitor Cells Enhance Neoangiogenesis of Human Pancreatic Islets
Microvesicles Derived From Endothelial Progenitor Cells Enhance Neoangiogenesis of Human Pancreatic Islets
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DOI：
10.3727/096368911x627534
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发表时间：
2012-01-01
影响因子：
3.3
通讯作者：
Camussi, Giovanni
中科院分区：
文献类型：
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作者：
Cantaluppi, Vincenzo;Biancone, Luigi;Camussi, Giovanni
胰岛移植的疗效因移植物血管化不良而受限。我们在此证明，内皮祖细胞（EPCs）释放的微泡（MVs）可增强人胰岛血管化。在融入胰岛内皮细胞和β细胞后，EPC衍生的MVs有利于胰岛素分泌、存活以及在SCID小鼠中移植的胰岛的血管重建。MVs在体外诱导胰岛内皮细胞增殖、迁移、抗凋亡以及形成血管样结构。此外，MVs部分克服了雷帕霉素的抗血管生成作用，并通过L -选择素和CD40抑制内皮白细胞相互作用。先前已表明MVs含有特定的mRNA模式。在此我们证明MVs携带促血管生成的miR - 126和miR - 296微小RNA（miRNAs）。用核糖核酸酶预处理的MVs或源自Dicer敲低的EPCs的MVs显示出血管生成作用降低。此外，MVs克服了miR - 126和miR - 296特异性拮抗剂的抗血管生成作用，表明MVs传递的miRNAs对胰岛内皮细胞有相关贡献。对MVs刺激的胰岛内皮细胞的微阵列分析表明，编码参与内皮细胞增殖、分化和血管生成的因子的mRNAs上调。此外，MVs诱导胰岛内皮细胞中PI3K - Akt和eNOS信号通路的激活。这些结果表明MVs激活胰岛内皮细胞中的血管生成程序，这可能维持血管重建和β细胞功能。
The efficacy of islet transplantation is limited by poor graft vascularization. We herein demonstrated that microvesicles (MVs) released from endothelial progenitor cells (EPCs) enhanced human islet vascularization. After incorporation into islet endothelium and beta-cells, EPC-derived MVs favored insulin secretion, survival, and revascularization of islets transplanted in SCID mice. MVs induced in vitro islet endothelial cell proliferation, migration, resistance to apoptosis, and organization in vessel-like structures. Moreover, MVs partially overcame the antiangiogenic effect of rapamycin and inhibited endothelial leukocyte interaction via L-selectin and CD40. MVs were previously shown to contain defined patterns of mRNAs. Here we demonstrated that MVs carried the proangiogenic miR- 126 and miR-296 microRNAs (miRNAs). MVs pretreated with RNase or derived from Dicer knocked-down EPCs showed a reduced angiogenic effect. In addition, MVs overcame the antiangiogenic effect of the specific antagomiRs of miR-126 and miR-296, suggesting a relevant contribution of miRNAs delivered by MVs to islet endothelium. Microarray analysis of MV-stimulated islet endothelium indicated the upregulation of mRNAs coding for factors involved in endothelial proliferation, differentiation, and angiogenesis. In addition, MVs induced the activation of the P13K-Akt and eNOS signaling pathways in islet endothelium. These results suggest that MVs activate an angiogenic program in islet endothelium that may sustain revascularization and beta-cell function.