title: Peripheral blood CD34+cells efficiently engraft human cytokine knock-in mice.
abstract: Human CD34+hematopoietic stem and progenitor cells (HSPCs) can reconstitute a human hemato-lymphoid system when transplanted into immunocompromised mice. Although fetal liver-derived and cord blood-derived CD34+cells lead to high engraftment levels, engraftment of mobilized, adult donor-derived CD34+cells has remained poor. We generated so-called MSTRG and MISTRG humanized mice on aRag2-/-Il2rg-/-background carrying a transgene for human signal regulatory protein α (SIRPα) and human homologs of the cytokine macrophage colony-stimulating factor, thrombopoietin, with or without interleukin-3 and granulocyte-macrophage colony-stimulating factor under murine promoters. Here we transplanted mobilized peripheral blood (PB) CD34+cells in sublethally irradiated newborn and adult recipients. Human hematopoietic engraftment levels were significantly higher in bone marrow (BM), spleen, and PB in newborn transplanted MSTRG/MISTRG as compared with nonobese diabetic/severe combined immunodeficientIl2rg-/-or human SIRPα-transgenicRag2-/-Il2rg-/-recipients. Furthermore, newborn transplanted MSTRG/MISTRG mice supported higher engraftment levels of human phenotypically defined HSPCs in BM, T cells in the thymus, and myeloid cells in nonhematopoietic organs such as liver, lung, colon, and skin, approximating the levels in the human system. Similar results were obtained in adult recipient mice. Thus, human cytokine knock-in mice might open new avenues for personalized studies of human pathophysiology of the hematopoietic and immune system in vivo.
authors.affiliation: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.|Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Yasuyuki
authors.identifier: 0000-0002-9291-1383
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Jana M
authors.initials: JM
authors.lastname: Ellegast
authors.affiliation: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Anahita
authors.initials: A
authors.lastname: Rafiei
authors.affiliation: Department of Immunobiology, Yale University, New Haven, CT.
authors.forename: Yuanbin
authors.initials: Y
authors.lastname: Song
authors.affiliation: Institute of Virology, Technische Universität München, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kull
authors.affiliation: Institute of Virology, Technische Universität München, Helmholtz Zentrum München, Munich, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Department of Immunobiology, Yale University, New Haven, CT.|Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Rongvaux
authors.affiliation: Section of Hematology, Department of Internal Medicine and.|Yale Cancer Center, Yale University School of Medicine, New Haven, CT; and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Halene
authors.affiliation: Department of Immunobiology, Yale University, New Haven, CT.|Howard Hughes Medical Institute, Yale University, New Haven, CT.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018952:Antigens, CD34 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D008221:Lymphoid Tissue / Q000378:metabolism; D008822:Mice, Transgenic
chemical_list: D018952:Antigens, CD34; D016207:Cytokines