title: Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment.
abstract: Current mouse lines efficient for human cell xenotransplantation are backcrossed into NOD mice to introduce its multiple immunodeficient phenotypes. Our positional genetic study has located the NOD-specific polymorphic Sirpa as a molecule responsible for its high xenograft efficiency: it recognizes human CD47 and the resultant signaling may cause NOD macrophages not to engulf human grafts. In the present study, we established C57BL/6.Rag2(nullIl2rgnull) mice harboring NOD-Sirpa (BRGS). BRGS mice engrafted human hematopoiesis with an efficiency that was equal to or even better than that of the NOD.Rag1(nullIl2rgnull) strain, one of the best xenograft models. Consequently, BRGS mice are free from other NOD-related abnormalities; for example, they have normalized C5 function that enables the evaluation of complement-dependent cytotoxicity of antibodies against human grafts in the humanized mouse model. Our data show that efficient human cell engraftment found in NOD-based models is mounted solely by their polymorphic Sirpa. The simplified BRGS line should be very useful in future studies of human stem cell biology.
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Katsuto
authors.initials: K
authors.lastname: Takenaka
authors.forename: Shingo
authors.initials: S
authors.lastname: Urata
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shima
authors.forename: Yoshikane
authors.initials: Y
authors.lastname: Kikushige
authors.forename: Takahito
authors.initials: T
authors.lastname: Tokuyama
authors.forename: Chika
authors.initials: C
authors.lastname: Iwamoto
authors.forename: Mariko
authors.initials: M
authors.lastname: Nishihara
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Nakayuki
authors.initials: N
authors.lastname: Honma
authors.forename: Miki
authors.initials: M
authors.lastname: Nakao
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
mesh_terms: D000818:Animals; D000910:Antibodies, Heterophile / Q000276:immunology; D051928:CD47 Antigen / Q000276:immunology / Q000378:metabolism; D019070:Cell Lineage / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006085:Graft Survival / Q000276:immunology; D006410:Hematopoiesis / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology*; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D023421:Models, Animal; D010587:Phagocytosis / Q000276:immunology; D011110:Polymorphism, Genetic / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000379:methods*
chemical_list: D000910:Antibodies, Heterophile; D051928:CD47 Antigen; C497894:CD47 protein, human; D004268:DNA-Binding Proteins; C501922:Sirpa protein, mouse; C499308:Rag2 protein, mouse; D011971:Receptors, Immunologic