Incorporation of CXCR4 into membrane hpid rafts primes homing-related responses of hematopoietic stem/progenitor cells to an SDF-1 gradient
Incorporation of CXCR4 into membrane hpid rafts primes homing-related responses of hematopoietic stem/progenitor cells to an SDF-1 gradient
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DOI：
10.1182/blood-2004-04-1430
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发表时间：
2005-01-01
期刊：
影响因子：
20.3
通讯作者：
Ratajczak, MZ
中科院分区：
文献类型：
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作者：
Wysoczynski, M;Reca, R;Ratajczak, MZ
我们发现用粒细胞集落刺激因子（G-CSF）或SLP的各种成分动员的患者的白细胞分离产物（SLP）的上清液（纤维蛋白原，纤连蛋白，可溶性血管细胞粘附分子-1 [VCAM-1]，细胞间粘附分子-1 [ICAM-1]，和尿激酶纤溶酶原激活物受体[uPAR]）增加造血干/祖细胞（HSPCs）对基质细胞的趋化反应。衍生因子-1（SDF-1）。然而，单独它们不化学吸引HSPC，但它们确实增加或引发细胞对低剂量或阈值剂量的SDF-1的趋化反应。我们观察到SLP增加了CD 34（+）细胞的钙流、丝裂原活化蛋白激酶（MAPK）p42/44和AKT的磷酸化、基质金属蛋白酶的分泌以及与内皮的粘附。此外，在NOD/SCID小鼠移植模型中，SLP增加了SDF依赖性肌动蛋白聚合，并显著增强了人脐带血（CB）和骨髓（BM）来源的CD 34（+）细胞的归巢。此外，细胞趋化性对SDF-1梯度的致敏或引发依赖于细胞膜中的胆固醇含量以及SDF-1结合受体CXCR 4和小GTCR-Rac-1掺入膜脂筏中。CXCR 4和Rac-1在脂筏中的这种共定位促进了Rac-1的三磷酸鸟苷（GTP）结合/活化。因此，我们假设CXCR 4可以通过与白细胞去除术和动员相关的各种因素引发，这些因素增加了CXCR 4与膜脂筏的结合，从而使HSPC能够更好地感知SDF-1梯度。这可能部分解释了为什么动员外周血白细胞去除产物的HSPC比BM或CB的HSPC更快地植入患者体内。根据我们的研究结果，我们认为，归巢的HSPCs是最佳的CXCR 4时，纳入膜脂筏和体外引发的HSPCs与一些SLP相关的分子移植前可以增加其植入。
We found that supernatants of leukapheresis products (SLPs) of patients mobilized with granulocyte-colony-stimulating factor (G-CSF) or the various components of SLPs (fibrinogen, fibronectin, soluble vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule-1 [ICAM-1], and urokinase plasminogen activator receptor [uPAR]) increase the chemotactic responses of hematopoietic stem/progenitor cells (HSPCs) to stromal-derived factor-1 (SDF-1). However, alone they do not chemoattract HSPCs, but they do increase or prime the cells' chemotactic responses to a low or threshold dose of SDF-1. We observed that SLPs increased calcium flux, phosphorylation of mitogen-activated protein kinase (MAPK) p42/44 and AKT, secretion of matrix metallo-proteinases, and adhesion to endothelium in CD34(+) cells. Furthermore, SLPs increased SDF-dependent actin polymerization and significantly enhanced the homing of human cord blood (CB)- and bone marrow (BM)-derived CD34(+) cells in a NOD/SCID mouse transplantation model. Moreover, the sensitization or priming of cell chemotaxis to an SDF-1 gradient was dependent on cholesterol content in the cell membrane and on the incorporation of the SDF-1 binding receptor CXCR4 and the small GTPase Rac-1 into membrane lipid rafts. This colocalization of CXCR4 and Rac-1 in lipid rafts facilitated guanosine triphosphate (GTP) binding/activation of Rac-1. Hence, we postulate that CXCR4 could be primed by various factors related to leukapheresis and mobilization that increase its association with membrane lipid rafts, allowing the HSPCs to better sense the SDF-1 gradient. This may partially explain why HSPCs from mobilized peripheral blood leukapheresis products engraft more quickly in patients than do those from BM or CB. Based on our findings, we suggest that the homing of HSPCs is optimal when CXCR4 is incorporated in membrane lipid rafts and that ex vivo priming of HSPCs with some of the SLP-related molecules before transplantation could increase their engraftment.