Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes
Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes
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DOI：
10.1038/nm1400
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发表时间：
2006-05-01
期刊：
影响因子：
82.9
通讯作者：
Rafii, Shahin
中科院分区：
文献类型：
--
作者：
Jin, David K.;Shido, Koji;Rafii, Shahin
造血细胞因子加速血运重建的机制尚不清楚。在这里，我们表明，细胞因子介导的血小板中SDF-1的释放和非内皮细胞CXCR4(+)VEGFR1（+）造血祖细胞（“血管细胞”）的募集的大小构成了血管重建的主要决定因素。可溶性kit -配体（sKitL）、血小板生成素（TPO，由Thpo编码）、红细胞生成素（EPO）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）在较小程度上诱导血小板释放SDF-1，通过动员CXCR4(+)VEGFR1（+）血管细胞增强新生血管。尽管在GM-CSF和G-CSF (Csf2（-/-)Csf3(-/-)）均缺乏的小鼠中，缺血后肢的血供重建部分减弱，但在skitl -缺陷的Mmp9（-/-）以及血小板减少性Thpo（-/-）和TPO受体缺陷（Mpl(-/-)）小鼠中，发现了新生血管的严重损伤。在Thpo（-/-）、Mpl（-/-）和Mmp9（-/-）小鼠中，sdf -1介导的血管细胞动员和并入缺血肢体的功能受损。将CXCR4(+)VEGFR1（+）血管细胞移植到Mmp9（-/-）小鼠中可恢复血运重建，而抑制CXCR4可消除细胞因子和vegf - a介导的CXCR4(+)VEGFR1（+）细胞的动员并抑制血管生成。总之，造血细胞因子通过血小板中SDF-1的分级部署，支持CXCR4(+)VEGFR1（+）血管细胞的动员和募集，而VEGFR1对于增强血管重建的血管生成能力至关重要。输送SDF- 1可能有效地恢复血管病变患者的血管生成。
The mechanisms through which hematopoietic cytokines accelerate revascularization are unknown. Here, we show that the magnitude of cytokine-mediated release of SDF-1 from platelets and the recruitment of nonendothelial CXCR4(+)VEGFR1(+) hematopoietic progenitors, 'hemangiocytes,' constitute the major determinant of revascularization. Soluble Kit-ligand (sKitL), thrombopoietin (TPO, encoded by Thpo) and, to a lesser extent, erythropoietin (EPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induced the release of SDF-1 from platelets, enhancing neovascularization through mobilization of CXCR4(+)VEGFR1(+) hemangiocytes. Although revascularization of ischemic hindlimbs was partially diminished in mice deficient in both GM-CSF and G-CSF (Csf2(-/-)Csf3(-/-)), profound impairment in neovascularization was detected in sKitL-deficient Mmp9(-/-) as well as thrombocytopenic Thpo(-/-) and TPO receptor-deficient (Mpl(-/-)) mice. SDF-1-mediated mobilization and incorporation of hemangiocytes into ischemic limbs were impaired in Thpo(-/-), Mpl(-/-) and Mmp9(-/-) mice. Transplantation of CXCR4(+)VEGFR1(+) hemangiocytes into Mmp9(-/-) mice restored revascularization, whereas inhibition of CXCR4 abrogated cytokine- and VEGF-A-mediated mobilization of CXCR4(+)VEGFR1(+) cells and suppressed angiogenesis. In conclusion, hematopoietic cytokines, through graded deployment of SDF-1 from platelets, support mobilization and recruitment of CXCR4(+)VEGFR1(+) hemangiocytes, whereas VEGFR1 is essential for their angiogenic competency for augmenting revascularization. Delivery of SDF- 1 may be effective in restoring angiogenesis in individuals with vasculopathies.