Burger Jan A, Spoo Anke, Dwenger Anne, Burger Meike, Behringer Dirk
Division of Haematology/Oncology, Department of Medicine, Freiburg University Hospital, Hugstetterstrasse 55, D-79106 Freiburg, Germany.
Br J Haematol. 2003 Aug;122(4):579-89. doi: 10.1046/j.1365-2141.2003.04466.x.
Marrow stromal cells play an important role in regulating the development and proliferation of haematopoietic stem cells (HSC) within the marrow microenvironment. However, the molecular mechanisms of stem cell-stromal cell interactions are not fully understood. We observed that mobilized peripheral blood and cord-blood-derived CD34+ progenitor cells, or CD34+ acute myeloid leukaemia (AML) cells spontaneously migrated beneath marrow stromal cells, an in vitro migration phenomenon termed pseudoemperipolesis. In contrast, the CD34+ myeloid leukaemia cell line, Kasumi-1, did not display pseudoemperipolesis. Cord blood CD34+ cells had a higher capacity than granulocyte-colony-stimulating-factor-mobilized CD34+ cells for pseudoemperipolesis (28.7 +/- 12%vs 18.1 +/- 6.1% of input cells within 24 h, mean +/- SD, n = 8), whereas 9.4 +/- 12.6% (mean +/- SD, n = 10) of input AML cells displayed this phenomenon. Pseudoemperipolesis of CD34+ progenitor and AML cells was significantly inhibited by pertussis toxin and antibodies to the CXCR4 chemokine receptor (CXCR4, CD184), but not control antibodies. Moreover, CD34+ and AML cell migration was significantly inhibited by a CS1 peptide that blocks alpha4beta1 integrin binding, but not by a control peptide, in which the fibronectin binding motif was scrambled. Pseudoemperipolesis was associated with an increased proliferation of migrated CD34+ progenitor cells but not AML cells within the stromal layer, demonstrated by cell cycle analysis and cell division tracking. We conclude that alpha4beta1 integrin binding and CXCR4 chemokine receptor activation are prerequisites for the migration of CD34+ haematopoietic progenitors and AML cells beneath marrow stromal cells. These observations suggest a central role of marrow stromal cells for HSC trafficking and homing within the marrow microenvironment.
骨髓基质细胞在骨髓微环境中调节造血干细胞（HSC）的发育和增殖方面发挥着重要作用。然而，干细胞与基质细胞相互作用的分子机制尚未完全明确。我们观察到，动员的外周血和脐带血来源的CD34 +祖细胞，或CD34 +急性髓系白血病（AML）细胞可自发迁移至骨髓基质细胞下方，这种体外迁移现象称为假包涵体形成。相比之下，CD34 +髓系白血病细胞系Kasumi-1未表现出假包涵体形成。脐带血CD34 +细胞比粒细胞集落刺激因子动员的CD34 +细胞具有更高的假包涵体形成能力（24小时内输入细胞的28.7 +/- 12%对18.1 +/- 6.1%，平均值 +/-标准差，n = 8），而9.4 +/- 12.6%（平均值 +/-标准差，n = 10）的输入AML细胞表现出这种现象。百日咳毒素和抗CXCR4趋化因子受体（CXCR4，CD184）的抗体可显著抑制CD34 +祖细胞和AML细胞的假包涵体形成，但对照抗体则无此作用。此外，一种阻断α4β1整合素结合的CS1肽可显著抑制CD34 +细胞和AML细胞的迁移，但对照肽（其中纤连蛋白结合基序被打乱）则无此作用。通过细胞周期分析和细胞分裂追踪表明，假包涵体形成与基质层内迁移的CD34 +祖细胞而非AML细胞的增殖增加有关。我们得出结论，α4β1整合素结合和CXCR4趋化因子受体激活是CD34 +造血祖细胞和AML细胞迁移至骨髓基质细胞下方的先决条件。这些观察结果表明骨髓基质细胞在HSC在骨髓微环境中的运输和归巢中起着核心作用。
