title: Engraftment of human HSCs in nonirradiated newborn NOD-scid IL2rγ null mice is enhanced by transgenic expression of membrane-bound human SCF.
abstract: Immunodeficient mice engrafted with human HSCs support multidisciplinary translational experimentation, including the study of human hematopoiesis. Heightened levels of human HSC engraftment are observed in immunodeficient mice expressing mutations in the IL2-receptor common γ chain (IL2rg) gene, including NOD-scid IL2rγ(null) (NSG) mice. Engraftment of human HSC requires preconditioning of immunodeficient recipients, usually with irradiation. Such preconditioning increases the expression of stem cell factor (SCF), which is critical for HSC engraftment, proliferation, and survival. We hypothesized that transgenic expression of human membrane-bound stem cell factor Tg(hu-mSCF)] would increase levels of human HSC engraftment in nonirradiated NSG mice and eliminate complications associated with irradiation. Surprisingly, detectable levels of human CD45(+) cell chimerism were observed after transplantation of cord blood-derived human HSCs into nonirradiated adult as well as newborn NSG mice. However, transgenic expression of human mSCF enabled heightened levels of human hematopoietic cell chimerism in the absence of irradiation. Moreover, nonirradiated NSG-Tg(hu-mSCF) mice engrafted as newborns with human HSCs rejected human skin grafts from a histoincompatible donor, indicating the development of a functional human immune system. These data provide a new immunodeficient mouse model that does not require irradiation preconditioning for human HSC engraftment and immune system development.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. michael.brehm@umassmed.edu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brehm
authors.forename: Waldemar J
authors.initials: WJ
authors.lastname: Racki
authors.forename: Jean
authors.initials: J
authors.lastname: Leif
authors.forename: Lisa
authors.initials: L
authors.lastname: Burzenski
authors.forename: Vishnu
authors.initials: V
authors.lastname: Hosur
authors.forename: Amber
authors.initials: A
authors.lastname: Wetmore
authors.forename: Bruce
authors.initials: B
authors.lastname: Gott
authors.forename: Mary
authors.initials: M
authors.lastname: Herlihy
authors.forename: Ronald
authors.initials: R
authors.lastname: Ignotz
authors.forename: Raymond
authors.initials: R
authors.lastname: Dunn
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000502:physiology*; D002469:Cell Separation; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism*; D018183:Transplantation Chimera / Q000502:physiology*; D023001:Transplantation Tolerance / Q000502:physiology
chemical_list: D019089:Stem Cell Factor