HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver
HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver
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DOI：
10.1172/jci200317902
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发表时间：
2003-07-01
影响因子：
15.9
通讯作者：
Lapidot, T
中科院分区：
文献类型：
--
作者：
Kollet, O;Shivtiel, S;Lapidot, T
造血干细胞很少有助于肝再生，然而，对它们归巢到肝脏的机制（这是关键的第一步）知之甚少。趋化因子基质细胞衍生因子-1（SDF-1）吸引人和鼠的祖细胞，由肝胆管上皮细胞表达。对SDF-1受体CXCR 4的中和作用可阻断人CD 34（+）造血祖细胞对小鼠肝脏的归巢和植入，而局部注射人SDF-1可增加其归巢。移植的人细胞位于胆管周围的簇中，靠近表达SDF-1的上皮细胞，并分化为白蛋白产生细胞。辐射或炎症增加了SDF-1水平，肝损伤诱导MMP-9活性，导致CXCR 4表达增加和SDF-1介导的造血祖细胞向肝脏的募集。出乎意料的是，肝损伤后增加的HGF促进了突起形成、CXCR 4上调和SDF-1介导的人CD 34（+）祖细胞定向迁移，并与干细胞因子协同作用。因此，应激诱导的信号，如SDF-1、MMP-9和HGF表达的增加，将具有造血和/或肝样潜能的人CD 34（+）祖细胞募集到NOD/SCID小鼠的肝脏。我们的研究结果表明，造血CD 34（+）/CXCR 4（+）细胞对来自非造血损伤器官的应激信号的响应潜力是组织靶向和修复的重要机制。
Hematopoietic stem cells rarely contribute to hepatic regeneration, however, the mechanisms governing their homing to the liver, which is a crucial first step, are poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1), which attracts human and murine progenitors, is expressed by liver bile duct epithelium. Neutralization of the SDF-1 receptor CXCR4 abolished homing and engraftment of the murine liver by human CD34(+) hematopoietic progenitors, while local injection of human SDF-1 increased their homing. Engrafted human cells were localized in clusters surrounding the bile ducts, in close proximity to SDF-1-expressing epithelial cells, and differentiated into albumin-producing cells. Irradiation or inflammation increased SDF-1 levels and hepatic injury induced MMP-9 activity, leading to both increased CXCR4 expression and SDF-1-mediated recruitment of hematopoietic progenitors to the liver. Unexpectedly, HGF, which is increased following liver injury, promoted protrusion formation, CXCR4 upregulation, and SDF-1-mediated directional migration by human CD34(+) progenitors, and synergized with stem cell factor. Thus, stress-induced signals, such as increased expression of SDF-1, MMP-9, and HGF, recruit human CD34(+) progenitors with hematopoietic and/or hepatic-like potential to the liver of NOD/SCID mice. Our results suggest the potential of hematopoietic CD34(+)/CXCR4(+) cells to respond to stress signals from non-hematopoietic injured organs as an important mechanism for tissue targeting and repair.