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Role of fibrinolytic factors in the regulation of hematopoiesis

纤溶因子在造血调节中的作用

基本信息

批准号：
17591011
负责人：
BEATE Heissig
金额：
$ 2.24万
依托单位：
Juntendo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

The overall question in the two-year study was to understand how proteases regulate bone marrow(BM)-derived hematopoietic and endothelial cell/stem cell mobilization. We focused on two proteolytic families, the fibrinolytic cascade and the matrix metalloproteinases (MMPs).The urokinase plasminogen activator receptor (uPAR), a ligand for the serine proteinase urokinase plasminogen activator (uPA) is involved in cell movement and is part of the fibrinolytic cascade. Quantitative analysis of plasma levels of soluble uPAR (suPAR) in patient plasma samples after G-CSF treatment indicated that suPAR plasma levels correlated to leukocyte counts, but not to CD34+ stem cell counts in the peripheral blood. Therefore we concluded that suPAR is not a good marker for stem cell mobilization.In another study we demonstrated that low-dose irradiation promotes endothelial progenitor cells (EPC)mobilization through MMP-9 mediated release of kit-ligand and VEGF release from mast cells.We also were able to demonstrate that G-CSF-driven muscle tissue regeneration was partly mediated by the mobilization of BM-derived EPCs and vascular endothelial growth factor (VEGF) released from neutrophils.In collaboration with the group of Dr. Raffi, we could show that CXCR4+/VEGF-receptor1+ BM-derived hemangiocytes promote cytokine-driven tissue regeneration.Taken together, proteases play a role in the stem cell mobilization process. They are critical in shedding/releasing extracellular-or membrane-bound growth factors resulting in their bioavailability.

这项为期两年的研究的总体问题是了解蛋白酶如何调节骨髓（BM）衍生的造血细胞和内皮细胞/干细胞的动员。我们重点研究了两个蛋白水解家族，纤溶级联和基质金属蛋白酶（MMPs）。尿激酶纤溶酶原激活剂受体（uPAR）是丝氨酸蛋白酶尿激酶纤溶酶原激活剂（uPA）的配体，参与细胞运动，是纤溶级联反应的一部分。定量分析G-CSF治疗后患者血浆样品中可溶性uPAR （suPAR）的血浆水平表明，suPAR血浆水平与外周血白细胞计数相关，而与外周血CD34+干细胞计数无关。因此，我们得出结论，suPAR不是干细胞动员的良好标记物。在另一项研究中，我们证明了低剂量照射通过MMP-9介导的kit配体释放和肥大细胞的VEGF释放促进内皮祖细胞（EPC）的动员。我们还能够证明g - csf驱动的肌肉组织再生部分是由bm来源的EPCs和中性粒细胞释放的血管内皮生长因子（VEGF）的动员介导的。通过与Raffi博士团队的合作，我们可以证明CXCR4+/ vegf受体1+ bm来源的血管细胞促进细胞因子驱动的组织再生。总之，蛋白酶在干细胞动员过程中发挥作用。它们在脱落/释放细胞外或膜结合生长因子导致其生物利用度方面至关重要。