Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1
Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1
复制标题
DOI：
10.1038/nm1075
复制
发表时间：
2004-08-01
期刊：
影响因子：
82.9
通讯作者：
Gurtner, GC
中科院分区：
文献类型：
--
作者：
Ceradini, DJ;Kulkarni, AR;Gurtner, GC
循环干细胞和祖细胞向组织损伤区域的迁移机制尚不清楚。趋化因子基质细胞衍生因子 - 1（SDF - 1或CXCL12）通过与循环细胞上的CXCR4结合，介导干细胞归巢到骨髓（1,2）。在胚胎器官发生过程中，SDF - 1和CXCR4以互补的模式表达，并引导原始干细胞到达血管快速扩张的部位（3）。然而，SDF - 1的调节及其在外周组织修复中的生理作用仍未完全明确（4）。在此我们表明，在内皮细胞中，SDF - 1基因表达受转录因子缺氧诱导因子 - 1（HIF - 1）的调节，导致SDF - 1在缺血组织中的体内选择性表达与氧张力降低成正比。HIF - 1诱导的SDF - 1表达增加了循环中CXCR4阳性祖细胞对缺血组织的黏附、迁移和归巢。阻断缺血组织中的SDF - 1或循环细胞上的CXCR4可阻止祖细胞募集到损伤部位。骨髓腔中局部缺氧区域也显示出SDF - 1表达增加和祖细胞趋向性。这些数据表明，CXCR4阳性祖细胞向再生组织的募集是通过缺氧梯度经由HIF - 1诱导的SDF - 1表达来介导的。
The trafficking of circulating stem and progenitor cells to areas of tissue damage is poorly understood. The chemokine stromal cell - derived factor-1 (SDF-1 or CXCL12) mediates homing of stem cells to bone marrow by binding to CXCR4 on circulating cells(1,2). SDF-1 and CXCR4 are expressed in complementary patterns during embryonic organogenesis and guide primordial stem cells to sites of rapid vascular expansion(3). However, the regulation of SDF-1 and its physiological role in peripheral tissue repair remain incompletely understood(4). Here we show that SDF-1 gene expression is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tissue in direct proportion to reduced oxygen tension. HIF-1-induced SDF-1 expression increases the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to ischemic tissue. Blockade of SDF-1 in ischemic tissue or CXCR4 on circulating cells prevents progenitor cell recruitment to sites of injury. Discrete regions of hypoxia in the bone marrow compartment also show increased SDF-1 expression and progenitor cell tropism. These data show that the recruitment of CXCR4-positive progenitor cells to regenerating tissues is mediated by hypoxic gradients via HIF-1-induced expression of SDF-1.