Induction of functional human macrophages from bone marrow promonocytes by M-CSF in humanized mice.
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.
Interdisciplinary Research Group in Infectious Diseases, Singapore-Massachusetts Institute of Technology Alliance for Research and Technology, Singapore 138602.
Yan
Y
Li
Qingfeng
Q
Chen
Dahai
D
Zheng
Lu
L
Yin
Yok Hian
YH
Chionh
Lan Hiong
LH
Wong
Shu Qi
SQ
Tan
Thiam Chye
TC
Tan
Jerry K Y
JK
Chan
Sylvie
S
Alonso
Peter C
PC
Dedon
Bing
B
Lim
Jianzhu
J
Chen
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology* / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D055017:Monocyte-Macrophage Precursor Cells / Q000166:cytology* / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016173:Macrophage Colony-Stimulating Factor