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PDF Attached ARTICLES Quantitative production of macrophages or neutrophils ex vivo using conditional Hoxb8 methods Gang G Wang1,2, Katherine R Calvo1,3, Martina P Pasillas1,DavidBSykes1,4, Hans Ha¨cker5 & Mark P Kamps1 Differentiation mechanisms and inflammatory functions of phagocyte functions, there is no simple protocol to generate large .com/nature e neutrophils and macrophages are usually studied by genetic and numbers of neutrophils or monocytes from these mutant mice to biochemical approaches that require costly breeding and characterize the impact of a genetic mutation on their differentia- .natur time-consuming purification to obtain phagocytes for functional tion, signal transduction or effector functions. w analysis. Because Hox oncoproteins enforce self-renewal of Class I Hox home domain transcription factors promote the factor-dependent myeloid progenitors, we queried whether expansion of hemopoietic progenitors, and their expression is estrogen-regulated Hoxb8 (ER-Hoxb8) could immortalize deregulated in both human and mouse myeloid leukemia. The http://ww macrophage or neutrophil progenitors that would execute normal abundance of Hoxa9 and Hoxa7 is high in CD34+, Sca-1+, lineage- differentiation and normal innate immune function upon negative (Lin–) bone marrow populations that are enriched in oup r G ER-Hoxb8 inactivation. Here we describe methods to derive hematopoietic stem cells (HSC) and in lineage-committed pro- unlimited quantities of mouse macrophages or neutrophils by genitors, and both are downregulated coincident with transition immortalizing their respective progenitors with ER-Hoxb8 using to the CD34– stage of early progenitor differentiation3,4. –/– lishing different cytokines to target expansion of different committed Hoxa9 mice have five- to tenfold fewer marrow HSC and b progenitors. ER-Hoxb8 neutrophils and macrophages are substantial reductions in myeloid and pre–B cell progenitors4, Pu functionally superior to those produced by many other ex vivo whereas retroviral expression of Hoxa9 produces a tenfold increase differentiation models, have strong inflammatory responses and in the number of long-term repopulating HSC (LT-HSC)5. Nature can be derived easily from embryonic day 13 (e13) fetal liver of Enforced production of Hoxb8 or Hoxa9 blocks differentiation of 6 mice exhibiting embryonic-lethal phenotypes. Using knockout or stem cell factor (SCF)- or granulocyte-macrophage colony-stimu- 6–9 200 small interfering RNA (siRNA) technologies, this ER-Hoxb8 lating factor (GM-CSF)–dependent myeloid progenitors . © phagocyte maturation system represents a rapid analytical tool Based on the ability of Hox proteins to arrest myeloid differ- for studying macrophage and neutrophil biology. entiation and permit infinite progenitor expansion, we asked whether factor-dependent hematopoietic progenitors immorta- Phagocytic cells and inflammation are important in immunologic lized by estrogen receptor fusions (conditional forms) of Hoxb8 regulation as well as in the pathology of chronic inflammatory or Hoxa9 could yield cell models of normal neutrophil- or macro- diseases (for example, multiple sclerosis, liver cirrhosis, arthritis, phage-restricted differentiation. By testing combinations of pro- atherosclerosis, diabetes, vascular diseases and inflammatory bowel genitor isolation protocols, cytokines used for pre-stimulation and disease) and acute inflammatory disease (for example, toxic shock long-term culture, and oncoprotein identity, we developed a simple syndrome). Normal inflammatory processes have also been linked and reliable protocol to derive macrophage-committed progenitor to complex diseases such as the proliferation and metastasis of lines and a second protocol to derive neutrophil-committed cancer1 and the development of obesity2. Understanding the progenitor lines. molecular mechanisms by which a phagocyte responds to chemo- Based on immunologic, functional and genetic criteria, the kines and cytokines, activates a proinflammatory cascade, mod- macrophages and neutrophils produced from these lines model ulates lymphocyte expansion and function, and effects microbial normal exit from the cell cycle, and acquisition of phagocytic and killing will ultimately reveal mechanisms of chronic inflammation, inflammatory functions. In response to Toll-receptor agonists, whereas identification of the genetic pathways that control phago- macrophages derived from ER-Hoxb8 progenitors upregulated cyte differentiation is important for understanding myeloid leuke- components of NF-kB signaling and downstream effectors genes mogenesis. Although the function of innate immune proteins can such as Il1, Il6, Ptgs2 and Tgm2. The ability of ER-Hoxb8 to drive be studied by knockout technologies that reveal their importance in progenitor expansion and permit their subsequent differentiation 1Department of Pathology & Molecular Pathology Graduate Program and 2Biomedical Sciences Graduate Program, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. 3Laboratory of Pathology, National Health Institutes, National Cancer Institute, 10 Center Drive, Bldg. 10, 2N212, Bethesda, Maryland 20892, USA. 4Department of Medicine, Harvard Massachusetts General Hospital, 55 Fruit Street, Boston Massachusetts 02114, USA. 5St. Jude Children’s Research Hospital, Department of Infectious Diseases, Room E8062, 332 North Lauderdale Street, Memphis, Tennessee 38105, USA. Correspondence should be addressed to M.P.K. ([email protected]). RECEIVED 19 DECEMBER 2005; ACCEPTED 13 FEBRUARY 2006; PUBLISHED ONLINE 22 MARCH 2006; DOI:10.1038/NMETH865 NATURE METHODS | VOL.3 NO.4 | APRIL 2006 | 287 ARTICLES Figure 1 | ER-Hoxb8 and ER-Hoxa9 function acERBD, 314 aa Hox d conditionally at the biochemical and cellular HD 14 Flag 9 levels. (a) Estrogen-binding domain (ERBD) Flag-ER-Hoxb8 Hoxa9 ER-Hoxa9 Hoxb8 ER-Hoxb8 ER-Hoxb8 + Es of the estrogen receptor fused to Hoxa9 or Hoxb8. EE ER-Hoxa9 + Es EE-ER-Hoxa9 12 ER-Hoxb8 – Es Epitope tags, Flag and Glu-Glu (EE) are indicated 8 ER-Hoxa9 – Es on the left. HD represents the home domain. b 10 9 10 (b) Concentration-dependent transcriptional 8 7 7 activity of ER-Hoxa9, measured as coactivation ER-Hoxb8 6 8 ER-Hoxa9 Log (cell number) 5 Log (cell number) through TGAT-TTAT motifs in cooperation with Vector only 4 6 E2a-Pbx1 in 293T cells. ER-Hoxb8 yielded a similar 3 concentration-dependent activation curve. activation Fold 2 6 1 (c) Immortalization kinetics of GM-CSF–dependent 0 5 11 10 9 8 76 1020 30 40 50 0 2 4 6 8 progenitors after infection by ER-Hoxa9 or ER- –Log [estrogen] Time (d) Time (d) methods Hoxb8 retrovirus in the presence of estrogen. Retroviral infection was performed at day 0, and dashed lines signify duration of selection in G418. Inserted panel represents a western blot using anti-Hoxa9 (left) and anti-Flag (right) on G418-selected, immortalized progenitors. Immortalization kinetics and doubling times were somewhat faster for progenitors derived in SCF. (d) Proliferation of GM-CSF–dependent progenitors immortalized by ER-Hoxa9 or ER-Hoxb8 in continued presence or after withdrawal of estrogen (ES) on day 0. .com/nature e to neutrophils or macrophages makes this model system an ideal ER-Hoxb8 immortalizes neutrophil or macrophage progenitors .natur w tool to study myeloid differentiation as well as cell biology and In the presence of 1 mM estrogen, infection of primary marrow inflammatory functions of macrophages and neutrophils. progenitors cultured in interleukin 3 (IL-3), SCF or GM-CSF with retrovirus expressing genes encoding ER-Hoxb8 or ER-Hoxa9 http://ww RESULTS produced immortalized factor-dependent progenitors (Fig. 1c), ER-Hoxb8 and ER-Hoxa9 exhibit estrogen-stimulated function which ceased proliferation (Fig. 1d) and exhibited terminal mor- oup We fused the estrogen-binding domain of the estrogen receptor phologic differentiation upon estrogen withdrawal (Fig. 2a). r G (ER) to the N terminus of Hoxb8 and Hoxa9, added N-terminal Progenitors were not immortalized when infections were per- epitope tags to facilitate subsequent identification, and expressed formed in the presence of granulocyte colony stimulating factor the fusion cDNAs using a murine stem cell virus (MSCV) retroviral (G-CSF) or macrophage colony stimulating factor (M-CSF). By lishing b expression vector (Fig. 1a). We measured estrogen-regulated tran- testing different progenitor isolation protocols, cell culture condi- Pu scriptional function of ER-Hoxb8 and ER-Hoxa9 by virtue of their tions and ER-Hox fusion oncoproteins, we determined conditions ability to cooperate with activated forms of Pbx to activate for derivation of cell lines demonstrating quantitative neutrophil transcription of a luciferase reporter driven by TGAT-TTAT Pbx- differentiation or quantitative macrophage differentiation. By using Nature Hox motifs. Using this assay, ER-Hoxa9 and ER-Hoxb8 exhibited negative selection (removing MacI+, B220+, Thy1.2+ cells) of total 6 estrogen-dependent transcriptional activation of ten- and bone marrow progenitors followed by a 2-d pre-expansion in SCF, 200 threefold, respectively, with half-maximal activation occurring at IL-3 and IL-6, and immortalization with ER-Hoxb8 retrovirus in © 10 nM estrogen (Fig. 1b). medium containing SCF as the only cytokine, immortalized abHoxb8-ER SCF Hoxb8-ER GM-CSF + Estrogen– Estrogen (6 d) + Estrogen – Estrogen (6 d) No Ab No Ab F4/80 F4/80 Phase contrast Gr-1 Gr-1 Wright-Giemsa Mac-1 Mac-1 markers Differentiation 100 101 102 103 104 100 101 102 103 104 Figure
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