MicroRNA126 通过降低血管细胞黏附分子 1 的表达促进粒细胞集落刺激因子诱导的造血祖细胞动员。
MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1.
机构信息
Laboratory of Cellular Oncology, CCR, NCI, NIH, Bethesda, MD 20892, USA.
出版信息
Haematologica. 2012 Jun;97(6):818-26. doi: 10.3324/haematol.2011.056945. Epub 2012 Jan 22.
BACKGROUND
Mobilization of hematopoietic stem/progenitor cells from the bone marrow to the peripheral blood by granulocyte colony-stimulating factor is the primary means to acquire stem cell grafts for hematopoietic cell transplantation. Since hematopoietic stem/progenitor cells represent a minority of all blood cells mobilized by granulocyte colony-stimulating factor, the underlying mechanisms need to be understood in order to develop selective drugs.
DESIGN AND METHODS
We analyzed phenotypic, biochemical and genetic changes in bone marrow cell populations from granulocyte colony-stimulating factor-mobilized and control mice, and linked such changes to effective mobilization of hematopoietic stem/progenitor cells.
RESULTS
We show that granulocyte colony-stimulating factor indirectly reduces expression of surface vascular cell adhesion molecule 1 on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells by promoting the accumulation of microRNA-126 (miR126)-containing microvescicles in the bone marrow extracellular compartment. We found that hematopoietic stem/progenitor cells, stromal cells and endothelial cells readily incorporate these miR126-loaded microvescicles, and that miR126 represses vascular cell adhesion molecule 1 expression on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells. In line with this, miR126-null mice displayed a reduced mobilization response to granulocyte colony-stimulating factor.
CONCLUSIONS
Our results implicate miR126 in the regulation of hematopoietic stem/progenitor cell trafficking between the bone marrow and peripheral sites, clarify the role of vascular cell adhesion molecule 1 in granulocyte colony-stimulating factor-mediated mobilization, and have important implications for improved approaches to selective mobilization of hematopoietic stem/progenitor cells.
背景
粒细胞集落刺激因子（G-CSF）将造血干细胞/祖细胞从骨髓动员到外周血是获取造血细胞移植干细胞移植物的主要手段。由于造血干细胞/祖细胞在 G-CSF 动员的所有血细胞中只占少数，因此需要了解其潜在机制，以便开发选择性药物。
设计与方法
我们分析了 G-CSF 动员和对照小鼠骨髓细胞群体的表型、生化和遗传变化，并将这些变化与造血干细胞/祖细胞的有效动员联系起来。
结果
我们表明，G-CSF 通过促进骨髓细胞外间隙中含有 microRNA-126（miR126）的微泡的积累，间接降低了骨髓造血干细胞/祖细胞、基质细胞和内皮细胞表面血管细胞黏附分子 1 的表达。我们发现造血干细胞/祖细胞、基质细胞和内皮细胞很容易摄取这些含有 miR126 的微泡，而 miR126 抑制了骨髓造血干细胞/祖细胞、基质细胞和内皮细胞表面血管细胞黏附分子 1 的表达。与此一致的是，miR126 缺失小鼠对 G-CSF 的动员反应降低。
结论
我们的结果表明 miR126 参与了造血干细胞/祖细胞在骨髓和外周部位之间的迁移调节，阐明了血管细胞黏附分子 1 在 G-CSF 介导的动员中的作用，对改善造血干细胞/祖细胞的选择性动员方法具有重要意义。
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