title: Efficient differentiation and function of human macrophages in humanized CSF-1 mice.
abstract: Humanized mouse models are useful tools to understand pathophysiology and to develop therapies for human diseases. While significant progress has been made in generating immunocompromised mice with a human hematopoietic system, there are still several shortcomings, one of which is poor human myelopoiesis. Here, we report that human CSF-1 knockin mice show augmented frequencies and functions of human myeloid cells. Insertion of human CSF1 into the corresponding mouse locus of Balb/c Rag2(-/-) γc(-/-) mice through VELOCIGENE technology resulted in faithful expression of human CSF-1 in these mice both qualitatively and quantitatively. Intra-hepatic transfer of human fetal liver derived hematopoietic stem and progenitor cells (CD34(+)) in humanized CSF-1 (CSF1(h/h)) newborn mice resulted in more efficient differentiation and enhanced frequencies of human monocytes/macrophages in the bone marrow, spleens, peripheral blood, lungs, liver and peritoneal cavity. Human monocytes/macrophages obtained from the humanized CSF-1 mice show augmented functional properties including migration, phagocytosis, activation and responses to LPS. Thus, humanized mice engineered to express human cytokines will significantly help to overcome the current technical challenges in the field. In addition, humanized CSF-1 mice will be a valuable experimental model to study human myeloid cell biology.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Chozhavendan
authors.initials: C
authors.lastname: Rathinam
authors.forename: William T
authors.initials: WT
authors.lastname: Poueymirou
authors.forename: Jose
authors.initials: J
authors.lastname: Rojas
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: David M
authors.initials: DM
authors.lastname: Valenzuela
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Anthony
authors.initials: A
authors.lastname: Rongvaux
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Eynon
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D004526:Efficiency; D055879:Gene Knock-In Techniques; D006801:Humans; D007142:Immunoglobulin gamma-Chains / Q000235:genetics; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D013045:Species Specificity
chemical_list: D004268:DNA-Binding Proteins; D007142:Immunoglobulin gamma-Chains; C499308:Rag2 protein, mouse; D016173:Macrophage Colony-Stimulating Factor