Karpova Darja, Ritchey Julie K, Holt Matthew S, Abou-Ezzi Grazia, Monlish Darlene, Batoon Lena, Millard Susan, Spohn Gabriele, Wiercinska Eliza, Chendamarai Ezhil, Yang Wei, Christ Stephanie, Gehrs Leah, Schuettpelz Laura G, Dembowsky Klaus, Pettit Allison R, Rettig Michael P, Bonig Halvard, DiPersio John F
Division of Oncology, Department of Medicine, and.
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
Blood. 2017 May 25;129(21):2939-2949. doi: 10.1182/blood-2016-10-746909. Epub 2017 Apr 11.
Interaction between the chemokine receptor CXCR4 and its chief ligand CXCL12 plays a critical role in the retention and migration of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) microenvironment. In this study, qualitative and quantitative effects of long-term pharmacologic inhibition of the CXCR4/CXCL12 axis on the HSPC compartment were investigated by using 3 structurally unrelated small molecule CXCR4 antagonists. A >10-fold increase in mobilization efficiency was achieved by administering the antagonists as a subcutaneous continuous infusion for 2 weeks compared to a single bolus injection. A concurrent increase in self-renewing proliferation leading to a twofold to fourfold expansion of the HSPC pool in the BM was observed. The expanded BM showed a distinct repopulating advantage when tested in serial competitive transplantation experiments. Furthermore, major changes within the HSPC niche associated with previously described HSPC expansion strategies were not detected in bones treated with a CXCR4 antagonist infusion. Our data suggest that prolonged but reversible pharmacologic blockade of the CXCR4/CXCL12 axis represents an approach that releases HSPC with efficiency superior to any other known mobilization strategy and may also serve as an effective method to expand the BM HSPC pool.
趋化因子受体CXCR4与其主要配体CXCL12之间的相互作用在造血干细胞和祖细胞（HSPCs）于骨髓（BM）微环境中的滞留和迁移过程中起着关键作用。在本研究中，我们使用3种结构不相关的小分子CXCR4拮抗剂，研究了长期药物抑制CXCR4/CXCL12轴对HSPC区室的定性和定量影响。与单次推注相比，通过皮下持续输注拮抗剂2周，动员效率提高了10倍以上。同时观察到自我更新增殖增加，导致BM中HSPC池扩大了2至4倍。在系列竞争性移植实验中测试时，扩大后的BM显示出明显的再增殖优势。此外，在用CXCR4拮抗剂输注处理的骨骼中，未检测到与先前描述的HSPC扩增策略相关的HSPC生态位内的主要变化。我们的数据表明，对CXCR4/CXCL12轴进行长期但可逆的药物阻断代表了一种释放HSPC的方法，其效率优于任何其他已知的动员策略，并且还可能作为扩大BM HSPC池的有效方法。
