Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice
Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice
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DOI：
10.4049/jimmunol.1300742
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发表时间：
2013-09-15
影响因子：
4.4
通讯作者：
Chen, Jianzhu
中科院分区：
文献类型：
--
作者：
Li, Yan;Chen, Qingfeng;Chen, Jianzhu
将人CD 34（+）造血干/祖细胞移植到免疫缺陷小鼠中导致人T和B细胞的稳健重建，但不导致单核细胞和巨噬细胞的重建。为了确定单核细胞和巨噬细胞重建不良的原因，我们分析了人源化小鼠中的人髓样细胞发育，发现其在骨髓中的前单核细胞阶段被阻断。人M-CSF或GM-CSF的表达，通过流体动力学注射的精氨酸编码质粒完全取消了前单核细胞在骨髓中的积累。M-CSF促进成熟单核细胞和组织驻留巨噬细胞的发育，而GM-CSF没有。此外，与感染部位的人巨噬细胞增加相关，M-CSF处理的人源化小鼠表现出增强的对流感病毒和分枝杆菌感染的保护。我们的研究确定了人源化小鼠中人单核细胞/巨噬细胞发育受阻的确切阶段，并揭示了M-CSF和GM-CSF在人单核细胞和巨噬细胞发育中的重叠和不同功能。在人源化小鼠中，M-CSF表达后单核细胞/巨噬细胞的重建和功能的改善为研究巨噬细胞在生理和病理过程中的作用提供了上级体内系统。
Engraftment of human CD34(+) hematopoietic stem/progenitor cells into immunodeficient mice leads to robust reconstitution of human T and B cells but not monocytes and macrophages. To identify the cause underlying the poor monocyte and macrophage reconstitution, we analyzed human myeloid cell development in humanized mice and found that it was blocked at the promonocyte stage in the bone marrow. Expression of human M-CSF or GM-CSF by hydrodynamic injection of cytokine-encoding plasmid completely abolished the accumulation of promonocytes in the bone marrow. M-CSF promoted the development of mature monocytes and tissue-resident macrophages whereas GM-CSF did not. Moreover, correlating with an increased human macrophages at the sites of infection, M-CSF-treated humanized mice exhibited an enhanced protection against influenza virus and Mycobacterium infection. Our study identifies the precise stage at which human monocyte/macrophage development is blocked in humanized mice and reveals overlapping and distinct functions of M-CSF and GM-CSF in human monocyte and macrophage development. The improved reconstitution and functionality of monocytes/macrophages in the humanized mice following M-CSF expression provide a superior in vivo system to investigate the role of macrophages in physiological and pathological processes.