Suppression of CXCL12 production by bone marrow osteoblasts is a common and critical pathway for cytokine-induced mobilization
Suppression of CXCL12 production by bone marrow osteoblasts is a common and critical pathway for cytokine-induced mobilization
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DOI：
10.1182/blood-2008-10-184754
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发表时间：
2009-08-13
期刊：
影响因子：
20.3
通讯作者：
Link, Daniel C.
中科院分区：
文献类型：
--
作者：
Christopher, Matthew J.;Liu, Fulu;Link, Daniel C.
目前的证据表明，粒细胞集落刺激因子(G-CSF)动员造血干/祖细胞(HSPC)是通过诱导骨髓中的蛋白水解酶、抑制黏附分子功能和破坏骨髓中的CXCL12/CXCR4信号通路来实现的。这些途径相互重叠或独立发挥作用的相对重要性和程度尚不确定。尽管有证据表明在骨髓中有蛋白酶激活，但在CXCR4(-/-)骨髓嵌合体中，G-CSF或趋化因子Groβ动员HSPC的作用被取消。相反，VLA-4拮抗剂对HSPC的动员是完整的。为了确定其他动员细胞因子是否干扰CXCR4信号转导，我们研究了Flt3配体(Flt3L)和干细胞因子(SCF)动员HSPC后CXCR4和CXCL12的表达。事实上，Flt3L或SCF治疗导致CXCL12在骨髓中的表达显著减少，并使HSPC上CXCR4的表面表达减少。RNA原位和分选实验表明，CXCL12表达的降低是成骨细胞系细胞丧失的继发原因。综上所述，这些数据表明，CXCR4信号的破坏和VLA-4功能的减弱是G-CSF动员的独立机制。成骨细胞表达CXCL12的缺失似乎是细胞因子诱导动员的常见和关键步骤。(血。2009；114：1331-1339)
Current evidence suggests that hematopoietic stem/progenitor cell (HSPC) mobilization by granulocyte colony-stimulating factor (G-CSF) is mediated by induction of bone marrow proteases, attenuation of adhesion molecule function, and disruption of CXCL12/CXCR4 signaling in the bone marrow. The relative importance and extent to which these pathways overlap or function independently are uncertain. Despite evidence of protease activation in the bone marrow, HSPC mobilization by G-CSF or the chemokine Gro beta was abrogated in CXCR4(-/-) bone marrow chimeras. In contrast, HSPC mobilization by a VLA-4 antagonist was intact. To determine whether other mobilizing cytokines disrupt CXCR4 signaling, we characterized CXCR4 and CXCL12 expression after HSPC mobilization with Flt3 ligand (Flt3L) and stem cell factor (SCF). Indeed, treatment with Flt3L or SCF resulted in a marked decrease in CXCL12 expression in the bone marrow and a loss of surface expression of CXCR4 on HSPCs. RNA in situ and sorting experiments suggested that the decreased CXCL12 expression is secondary to a loss of osteoblast lineage cells. Collectively, these data suggest that disruption of CXCR4 signaling and attenuation of VLA-4 function are independent mechanisms of mobilization by G-CSF. Loss of CXCL12 expression by osteoblast appears to be a common and key step in cytokine-induced mobilization. (Blood. 2009;114:1331-1339)