Constitutive Expression of HIF-1α and HIF-2α in Bone Marrow Stromal Cells Differentially Promotes Their Proangiogenic Properties
Constitutive Expression of HIF-1α and HIF-2α in Bone Marrow Stromal Cells Differentially Promotes Their Proangiogenic Properties
复制标题
DOI：
10.1634/stemcells.2008-0369
复制
发表时间：
2008-01-01
期刊：
影响因子：
5.2
通讯作者：
George, Jacob
中科院分区：
文献类型：
--
作者：
Ben-Shoshan, Jeremy;Schwartz, Shulamit;George, Jacob
骨髓基质细胞（BMSCs）含有能够参与出生后血管生成的祖细胞。缺氧诱导因子（HIF）通过驱动多种血管生成因子的表达来介导内皮激活。我们探索了HIF-1 α和HIF-2 α修饰BMSCs的潜力，作为改善基于细胞的血管生成治疗的工具。逆转录病毒转导BMSC以表达稳定形式的HIF-1 α和HIF-2 α。HIF-1 α和HIF-2 α在更大程度上的过表达促进了BMSC向内皮细胞系的分化，这通过CD 31和Tie-2表达和改善的粘附特性来证明。尽管在表达HIF-α的BMSCs中，对基质衍生因子1的趋化性更高，但只有在HIF-2 α过表达后，才发现向血管内皮生长因子的迁移增强，这得到了其受体Flk-1的强表达的支持。HIF-α表达与血管生成蛋白的上调和管形成的改善相关。从表达HIF-α的BMSC收集的培养基刺激的内皮细胞的细胞因子阵列显示进一步的血管生成激活和改善的粘附能力。最终，在角膜微囊血管生成模型中，与假转导或HIF-1 α转导的BMSC相比，HIF-2 α转导的BMSC的递送诱导了更强的血管生成反应。我们的研究结果支持使用HIF-α基因，特别是HIF-2 α，以增强未来基于细胞的治疗的疗效。干细胞2008; 26：2634-2643
Bone marrow stromal cells (BMSCs) contain progenitors capable of participating in postnatal angiogenesis. Hypoxia-inducible factors (HIFs) mediate endothelial activation by driving the expression of multiple angiogenic factors. We explored the potential of HIF-1 alpha and HIF-2 alpha modification in BMSCs, as a tool to improve cell-based angiogenic therapy. BMSCs were retrovirally transduced to express stable forms of HIF-1 alpha and HIF-2 alpha. HIF-1 alpha and, to a greater extent, HIF-2 alpha overexpression promoted differentiation of BMSCs to the endothelial lineage, evident by CD31 and Tie-2 expression and improved adhesive properties. Whereas chemotaxis toward stromal-derived factor 1 was higher in both HIF-alpha-expressing BMSCs, enhanced migration toward vascular endothelial growth factor was found only following overexpression of HIF-2 alpha, supported by a robust expression of its receptor, Flk-1. HIF-alpha expression was associated with upregulation of angiogenic proteins and improved tube formation. Cytokine arrays of endothelial cells stimulated by medium collected from HIF-alpha-expressing BMSCs revealed further angiogenic activation and improved adhesive capacity. Eventually, delivery of HIF-2 alpha-transduced BMSCs induced a more robust angiogenic response, compared with sham-transduced or HIF-1 alpha-transduced BMSCs in the corneal micropocket angiogenesis model. Our results support the use of HIF-alpha genes, particularly HIF-2 alpha, to augment the efficacy of future cell-based therapy. STEM CELLS 2008; 26: 2634-2643