The bone marrow hematopoietic microenvironment is impaired in iron-overloaded mice
The bone marrow hematopoietic microenvironment is impaired in iron-overloaded mice
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DOI：
10.1111/ejh.12309
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发表时间：
2014-08-01
影响因子：
3.1
通讯作者：
Ozawa, Keiya
中科院分区：
文献类型：
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作者：
Okabe, Hiroshi;Suzuki, Takahiro;Ozawa, Keiya
目的：越来越多的报道描述了铁超载患者铁络合治疗后的造血功能改善。这些观察表明，过量的铁可能会对造血产生不利影响。为了研究过量铁如何影响体内的造血，我们培育了铁超载的小鼠，并检测了这些小鼠的造血参数。方法：向C57BL/6J小鼠体内注射200 mg右旋糖酐铁建立铁超负荷小鼠，通过流式细胞术、集落形成实验和骨髓移植实验对小鼠骨髓中未成熟的造血细胞进行鉴定。我们还检测了造血微环境的分子图谱的变化。结果和结论：铁超载(IO)小鼠外周血造血数据未见明显缺陷。IO组小鼠骨髓中髓系祖细胞增多，但对红系祖细胞和造血干细胞的数量和功能无明显影响。然而，从正常供者到IO受者的骨髓移植显示出造血重建的延迟，这表明过量的铁对造血微环境产生了负面影响。基因芯片和定量RT-PCR分析显示，铁超载小鼠骨髓基质细胞CXCL12、VCAM-1、Kit-Ligand和IGF-1的表达显著降低。此外，IO骨髓和肝脏中的红细胞生成素和血小板生成素水平受到显著抑制，氧化应激增加。因此，我们的发现表明，过量的铁可以损害骨髓基质细胞和其他重要器官，可能是通过增加氧化应激来扰乱造血。
Objectives: Increasing numbers of reports have described hematopoietic improvement after iron chelation therapy in iron-overloaded patients. These observations indicate that excess iron could affect hematopoiesis unfavorably. To investigate how excess iron affects hematopoiesis in vivo, we generated iron-overloaded mice and examined hematopoietic parameters in these mice. Methods: We generated iron-overloaded mice by injecting 200 mg of iron dextran into C57BL/6J mice, and immature hematopoietic cells in the bone marrow were evaluated by flow cytometric analyses, colony-forming assays, and bone marrow transplantation analyses. We also examined changes in molecular profiles of the hematopoietic microenvironment. Results and Conclusions: Iron-overloaded (IO) mice did not show significant defects in the hematopoietic data of the peripheral blood. Myeloid progenitor cells in the bone marrow were increased in IO mice, but the number and function of the erythroid progenitors and hematopoietic stem cells were not significantly affected. However, bone marrow transplantation from normal donors to IO recipients showed delayed hematopoietic reconstitution, which indicates that excess iron impacts the hematopoietic microenvironment negatively. Microarray and quantitative RT-PCR analyses on the bone marrow stromal cells demonstrated remarkably reduced expression of CXCL12, VCAM-1, Kit-ligand, and IGF-1 in the iron-overloaded mice. In addition, erythropoietin and thrombopoietin levels were significantly suppressed, and increased oxidative stress was observed in the IO bone marrow and liver. Consequently, our findings indicate that excess iron can damage bone marrow stromal cells and other vital organs, disrupting hematopoiesis presumably by increased oxidative stress.