The sphingosine 1-phosphate receptor agonist FTY720 supports CXCR4-dependent migration and bone marrow homing of human CD34+ progenitor cells
The sphingosine 1-phosphate receptor agonist FTY720 supports CXCR4-dependent migration and bone marrow homing of human CD34+ progenitor cells
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DOI：
10.1182/blood-2003-03-0875
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发表时间：
2004-06-15
期刊：
影响因子：
20.3
通讯作者：
Möhie, R
中科院分区：
文献类型：
--
作者：
Kimura, T;Boehmier, AM;Möhie, R
新型免疫抑制剂 FTY720 激活 1-磷酸鞘氨醇受体 (S1PR)，影响淋巴细胞对基质细胞衍生因子 1 (SDF-1) 等趋化因子的反应，从而增加淋巴细胞归巢至次级淋巴器官。由于 SDF-1 及其受体 CXCR4 也参与造血干细胞和祖细胞 (HPC) 的骨髓 (BM) 归巢，因此我们分析了 S1PR 的表达以及 FTY720 对人 HPC 中 SDF-1/CXCR4 介导的作用的影响。通过逆转录聚合酶链式反应（RT-PCR），S1PRs在动员的CD34（+）HPCs中表达，特别是在原始CD34（+）/CD38（-）细胞中。 HPC 与 FTY720 一起孵育可延长 SDF-1 诱导的钙动员和肌动蛋白聚合，并显着增加 SDF-1 依赖性体外跨内皮迁移，而不影响 VLA-4、VLA-5 和 CXCR4 表达。在非肥胖糖尿病-严重联合免疫缺陷（NOD/SCID）小鼠中，通过用FTY720预处理动物和细胞，18小时后归巢到BM的CD34（+）/CD38（-）细胞数量显着增加；倾向于导致改善的植入。此外，HPC（第 5 周鹅卵石区域形成细胞 [CAFC]）的体外生长增加了 2.4 倍。我们得出的结论是，FTY720 激活 S1PR 会在体外和体内增加 HPC 中的 CXCR4 功能，支持 HPC 的归巢和增殖。在造血微环境中，S1PR 通过调节 SDF-1 的作用参与 HPC 的迁移和维持。 (C) 2004 年，美国血液学会。
The novel immunosuppressant FTY720 activates sphingosine 1-phosphate receptors (S1PRs) that affect responsiveness of lymphocytes to chemokines such as stromal cell-derived factor 1 (SDF-1), resulting in increased lymphocyte homing to secondary lymphoid organs. Since SDF-1 and its receptor CXCR4 are also involved in bone marrow (BM) homing of hematopoietic stem and progenitor cells (HPCs), we analyzed expression of S1PRs and the influence of FTY720 on SDF-1/ CXCR4-mediated effects in human HPCs. By reverse transcriptase-polymerase chain reaction (RT-PCR), S1PRs were ex- pressed in mobilized CD34(+) HPCs, particularly in primitive CD34(+)/CD38(-) cells. Incubation of HPCs with FTY720 resulted in prolonged SDF-1-induced calcium mobilization and actin polymerization, and substantially increased SDF-1-dependent in vitro transendothelial migration, without affecting VLA-4, VLA-5, and CXCR4 expression. In nonobese diabetic-severe combined immunodeficient (NOD/ SCID) mice, the number of CD34(+)/CD38(-) cells that homed to the BM after 18 hours was significantly raised by pretreatment of animals and cells with FTY720; tending to result in improved engraftment. In addition tion, in vitro growth of HPCs (week-5 cobblestone area-forming cells [CAFCs]) was 2.4-fold increased. We conclude that activation of S1PRs by FTY720 increases CXCR4 function in HPCs both in vitro and in vivo, supporting homing and proliferation of HPCs. In the hematopoietic microenvironment, S1PRs are involved in migration and maintenance of HPCs by modulating the effects of SDF-1. (C) 2004 by The American Society of Hematology.