Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors
Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors
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DOI：
10.1634/stemcells.2005-0319
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发表时间：
2006-04-01
期刊：
影响因子：
5.2
通讯作者：
Silberstein, Leslie E.
中科院分区：
文献类型：
--
作者：
Honczarenko, Marek;Le, Yi;Silberstein, Leslie E.
从骨髓中分离的基质细胞（BMSC）通常被称为间充质干细胞，目前正在研究其多种治疗应用。然而，关于可以影响其在骨髓中归巢和定位的受体的数据有限。在本研究中，我们发现第二代BMSCs表达一组独特的趋化因子受体：三种CC趋化因子受体（CCR1、CCR7和CCR9）和三种CXC趋化因子受体（CXCR4、CXCR5和CXCR6）。在无血清培养基中培养的 BMSC 分泌多种趋化因子配体（CCL2、CCL4、CCL5、CCL20、CXCL12、CXCL8 和 CX(3)CL1）。根据几个标准，表面表达的趋化因子受体具有功能。用趋化因子配体刺激 BMSC 会触发丝裂原激活蛋白激酶（例如细胞外信号相关激酶 [ERK]-1 和 ERK-2）和粘着斑激酶信号通路的磷酸化。此外，CXCL12 选择性激活信号转导子和转录激活子 (STAT)-5，而 CCL5 激活 STAT-1。在细胞生物学测定中，所有测试的趋化因子都会刺激 BMSC 的趋化性，并且 CXCL12 会诱导细胞骨架 F-肌动蛋白聚合。对培养扩增的 BMSC 的研究（例如 12-16 代）表明所有趋化因子受体的表面表达均丧失，并且缺乏对趋化因子的趋化反应。趋化因子受体表达的丧失伴随着粘附分子（ICAM-1、ICAM-2和血管细胞粘附分子1）和CD157表达的减少，而CD90和CD105的表达保持不变。 BMSC 表型的变化与细胞生长减慢和自发凋亡增加有关。这些发现表明，多种趋化因子轴可能在 BMSC 生物学中发挥作用，并且可能是验证用于细胞治疗的培养 BMSC 的重要参数。
Stromal cells isolated from bone marrow (BMSCs), often referred to as mesenchymal stem cells, are currently under investigation for a variety of therapeutic applications. However, limited data are available regarding receptors that can influence their homing to and positioning within the bone marrow. In the present study, we found that second passage BMSCs express a unique set of chemokine receptors: three CC chemokine receptors (CCR1, CCR7, and CCR9) and three CXC chemokine receptors (CXCR4, CXCR5, and CXCR6). BMSCs cultured in serum-free medium secrete several chemokine ligands (CCL2, CCL4, CCL5, CCL20, CXCL12, CXCL8, and CX(3)CL1). The surface-expressed chemokine receptors were functional by several criteria. Stimulation of BMSCs with chemokine ligands triggers phosphorylation of the mitogen-activated protein kinase (e.g., extracellular signal-related kinase [ERK]-1 and ERK-2) and focal adhesion kinase signaling pathways. In addition, CXCL12 selectively activates signal transducer and activator of transcription (STAT)-5 whereas CCL5 activates STAT-1. In cell biologic assays, all of the chemokines tested stimulate chemotaxis of BMSCs, and CXCL12 induces cytoskeleton F-actin polymerization. Studies of culture-expanded BMSCs, for example, 12-16 passages, indicate loss of surface expression of all chemokine receptors and lack of chemotactic response to chemokines. The loss in chemokine receptor expression is accompanied by a decrease in expression of adhesion molecules (ICAM-1, ICAM-2, and vascular cell adhesion molecule 1) and CD157, while expression of CD90 and CD105 is maintained. The change in BMSC phenotype is associated with slowing of cell growth and increased spontaneous apoptosis. These findings suggest that several chemokine axes may operate in BMSC biology and may be important parameters in the validation of cultured BMSCs intended for cell therapy.