Interdisciplinary Research Group in Infectious Diseases, Singapore-Massachusetts Institute of Technology Alliance for Research and Technology, Singapore 138602.
J Immunol. 2013 Sep 15;191(6):3192-9. doi: 10.4049/jimmunol.1300742. Epub 2013 Aug 9.
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.
将人源 CD34⁺ 造血干/祖细胞植入免疫缺陷小鼠中会导致人源 T 和 B 细胞的大量重建，但不会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系细胞发育情况，发现其在骨髓中于前单核细胞阶段受阻。通过水动力注射细胞因子编码质粒表达人源 M-CSF 或 GM-CSF 可完全消除骨髓中前单核细胞的积累。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 则不能。此外，与感染部位人源巨噬细胞增加相关的是，经 M-CSF 处理的人源化小鼠对流感病毒和分枝杆菌感染的保护作用增强。本研究确定了人源化小鼠中人类单核细胞/巨噬细胞发育受阻的精确阶段，并揭示了 M-CSF 和 GM-CSF 在人类单核细胞和巨噬细胞发育中的重叠和独特功能。在表达 M-CSF 后，人源化小鼠中单核细胞/巨噬细胞的重建和功能得到改善，为研究巨噬细胞在生理和病理过程中的作用提供了一个优越的体内系统。
