Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Engineering humanized mice for improved hematopoietic reconstitution

Abstract

Humanized mice are immunodeficient animals engrafted with human hematopoietic stem cells that give rise to various lineages of human blood cells throughout the life of the mouse. This article reviews recent advances in the generation of humanized mice, focusing on practical considerations. We discuss features of different immunodeficient recipient mouse strains, sources of human hematopoietic stem cells, advances in expansion and genetic modification of hematopoietic stem cells, and techniques to modulate the cytokine environment of recipient mice, in order to enhance reconstitution of specific human blood lineage cells. We highlight the opportunities created by new technologies and discuss practical considerations on how to make best use of the widening array of basic models for specific research applications.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

References

  1. Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K et al. NOD/SCID/γcnull mouse: an excellent recipient mouse model for engraftment of human cells. Blood 2002; 100: 3175–3182.

    CAS  PubMed  Google Scholar 

  2. Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti JC, Lanzavecchia A et al. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 2004; 304: 104–107.

    Article  CAS  PubMed  Google Scholar 

  3. Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G et al. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor γ chainnull mice. Blood 2005; 106: 1565–1573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R γnull mice engrafted with mobilized human hemopoietic stem cells. J Immunol. 2005; 174: 6477–6489.

    CAS  PubMed  Google Scholar 

  5. McDermott SP, Eppert K, Lechman ER, Doedens M, Dick JE . Comparison of human cord blood engraftment between immunocompromised mouse strains. Blood 2010; 116: 193–200.

    CAS  PubMed  Google Scholar 

  6. Chen Q, Khoury M, Chen J . Expression of human cytokines dramatically improves reconstitution of specific human-blood lineage cells in humanized mice. Proc Natl Acad Sci USA 2009; 106: 21783–21788.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Shultz LD, Ishikawa F, Greiner DL . Humanized mice in translational biomedical research. Nat Rev Immunol 2007; 7: 118–130.

    CAS  PubMed  Google Scholar 

  8. Billerbeck E, Barry WT, Mu K, Dorner M, Rice CM, Ploss A . Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor-, granulocyte–macrophage colony-stimulating factor-, and interleukin-3-expressing NOD-SCID IL2Rγnull humanized mice. Blood 2011; 117: 3076–3086.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Rongvaux A, Willinger T, Takizawa H, Rathinam C, Auerbach W, Murphy AJ et al. Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo. Proc Natl Acad Sci USA 2011; 108: 2378–2383.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Willinger T, Rongvaux A, Takizawa H, Yancopoulos GD, Valenzuela DM, Murphy AJ et al. Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung. Proc Natl Acad Sci USA 2011; 108: 2390–2395.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Rathinam C, Poueymirou WT, Rojas J, Murphy AJ, Valenzuela DM, Yancopoulos GD et al. Efficient differentiation and function of human macrophages in humanized CSF-1 mice. Blood 2011; 118: 3119–3128.

    CAS  PubMed  Google Scholar 

  12. Shultz LD, Saito Y, Najima Y, Tanaka S, Ochi T, Tomizawa M et al. Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r γnull humanized mice. Proc Natl Acad Sci USA 2010; 107: 13022–13027.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Jaiswal S, Pearson T, Friberg H, Shultz LD, Greiner DL, Rothman AL et al. Dengue virus infection and virus-specific HLA-A2 restricted immune responses in humanized NOD-scid IL2rγnull mice. PLoS One 2009; 4: e7251.

    PubMed  PubMed Central  Google Scholar 

  14. Danner R, Chaudhari SN, Rosenberger J, Surls J, Richie TL, Brumeanu TD et al. Expression of HLA class II molecules in humanized NOD.Rag1KO. IL2RgcKO mice is critical for development and function of human T and B cells. PLoS One 2011; 6: e19826.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Covassin L, Laning J, Abdi R, Langevin DL, Phillips NE, Shultz LD et al. Human peripheral blood CD4 T cell-engrafted non-obese diabetic-scid IL2rγnull H2-Ab1 (tm1Gru) Tg (human leucocyte antigen D-related 4) mice: a mouse model of human allogeneic graft-versus-host disease. Clin Exp Immunol 2011; 166: 269–280.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Takenaka K, Prasolava TK, Wang JC, Mortin-Toth SM, Khalouei S, Gan OI et al. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat Immunol 2007; 8: 1313–1323.

    CAS  PubMed  Google Scholar 

  17. Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 2010; 142: 699–713.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD Jr et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 2009; 138: 286–299.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 2009; 138: 271–285.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Strowig T, Rongvaux A, Rathinam C, Takizawa H, Borsotti C, Philbrick W et al. Transgenic expression of human signal regulatory protein alpha in Rag2−/−γc−/− mice improves engraftment of human hematopoietic cells in humanized mice. Proc Natl Acad Sci USA 2011; 108: 13218–13223.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE . Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science 2011; 333: 218–21.

    CAS  PubMed  Google Scholar 

  22. Majeti R, Park CY, Weissman IL . Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood. Cell Stem Cell 2007; 1: 635–645.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Drake AC, Khoury M, Leskov I, Iliopoulou BP, Fragoso M, Lodish H et al. Human CD34+CD133+ hematopoietic stem cells cultured with growth factors including Angptl5 efficiently engraft adult NOD-SCID Il2rγ−/− (NSG) mice. PLoS One 2011; 6: e18382.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. de Wynter EA, Buck D, Hart C, Heywood R, Coutinho LH, Clayton A et al. CD34+AC133+ cells isolated from cord blood are highly enriched in long-term culture-initiating cells, NOD/SCID-repopulating cells and dendritic cell progenitors. Stem Cells 1998; 16: 387–396.

    CAS  PubMed  Google Scholar 

  25. Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG et al. AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 1997; 90: 5002–5012.

    CAS  PubMed  Google Scholar 

  26. Matsumura T, Kametani Y, Ando K, Hirano Y, Katano I, Ito R et al. Functional CD5+ B cells develop predominantly in the spleen of NOD/SCID/γcnull (NOG) mice transplanted either with human umbilical cord blood, bone marrow, or mobilized peripheral blood CD34+ cells. Exp Hematol 2003; 31: 789–797.

    PubMed  Google Scholar 

  27. Hayakawa J, Hsieh MM, Uchida N, Phang O, Tisdale JF . Busulfan produces efficient human cell engraftment in NOD/LtSz-Scid IL2Rγnull mice. Stem Cells 2009; 27: 175–182.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang L, Kovalev GI, Su L . HIV-1 infection and pathogenesis in a novel humanized mouse model. Blood 2007; 109: 2978–2981.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Jiang Q, Zhang L, Wang R, Jeffrey J, Washburn ML, Brouwer D et al. FoxP3+CD4+ regulatory T cells play an important role in acute HIV-1 infection in humanized Rag2−/−γC−/− mice in vivo. Blood 2008; 112: 2858–2868.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang CC, Lodish HF . Cytokines regulating hematopoietic stem cell function. Curr Opin Hematol 2008; 15: 307–311.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Koestenbauer S, Zisch A, Dohr G, Zech NH . Protocols for hematopoietic stem cell expansion from umbilical cord blood. Cell Transplant 2009; 18: 1059–1068.

    PubMed  Google Scholar 

  32. Dahlberg A, Delaney C, Bernstein ID . Ex vivo expansion of human hematopoietic stem and progenitor cells. Blood 2011; 117: 6083–6090.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Giassi LJ, Pearson T, Shultz LD, Laning J, Biber K, Kraus M et al. Expanded CD34+ human umbilical cord blood cells generate multiple lymphohematopoietic lineages in NOD-scid IL2rγnull mice. Exp Biol Med (Maywood) 2008; 233: 997–1012.

    CAS  Google Scholar 

  34. Khoury M, Drake A, Chen Q, Dong D, Leskov I, Fragoso MF et al. Mesenchymal stem cells secreting angiopoietin-like-5 support efficient expansion of human hematopoietic stem cells without compromising their repopulating potential. Stem Cells Dev 2011; 20: 1371–1381.

    CAS  PubMed  Google Scholar 

  35. Zhang CC, Kaba M, Iizuka S, Huynh H, Lodish HF . Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation. Blood 2008; 111: 3415–3423.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 2010; 329: 1345–1348.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Chou S, Chu P, Hwang W, Lodish H . Expansion of human cord blood hematopoietic stem cells for transplantation. Cell Stem Cell 2010; 7: 427–428.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, Bernstein ID . Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med 2010; 16: 232–236.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Himburg HA, Muramoto GG, Daher P, Meadows SK, Russell JL, Doan P et al. Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nat Med 2010; 16: 475–482.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Yang H, Robinson SN, Lu J, Decker WK, Xing D, Steiner D et al. CD3+ and/or CD14+ depletion from cord blood mononuclear cells before ex vivo expansion culture improves total nucleated cell and CD34+ cell yields. Bone Marrow Transplant 2010; 45: 1000–1007.

    CAS  PubMed  Google Scholar 

  41. Frecha C, Costa C, Negre D, Amirache F, Trono D, Rio P et al. A novel lentivector targets gene transfer into hHSC in marrow from patients with BM-failure-syndrome and in vivo in humanized mice. Blood 2012; 119: 1139–1150.

    CAS  PubMed  Google Scholar 

  42. Novershtern N, Subramanian A, Lawton LN, Mak RH, Haining WN, McConkey ME et al. Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 2011; 144: 296–309.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Alexander IE, Russell DW, Miller AD . Transfer of contaminants in adeno-associated virus vector stocks can mimic transduction and lead to artifactual results. Hum Gene Ther 1997; 8: 1911–1920.

    CAS  PubMed  Google Scholar 

  44. Zhou SZ, Cooper S, Kang LY, Ruggieri L, Heimfeld S, Srivastava A et al. Adeno-associated virus 2-mediated high efficiency gene transfer into immature and mature subsets of hematopoietic progenitor cells in human umbilical cord blood. J Exp Med 1994; 179: 1867–1875.

    CAS  PubMed  Google Scholar 

  45. Nathwani AC, Hanawa H, Vandergriff J, Kelly P, Vanin EF, Nienhuis AW . Efficient gene transfer into human cord blood CD34+ cells and the CD34+CD38 subset using highly purified recombinant adeno-associated viral vector preparations that are free of helper virus and wild-type AAV. Gene Ther 2000; 7: 183–195.

    CAS  PubMed  Google Scholar 

  46. Santat L, Paz H, Wong C, Li L, Macer J, Forman S et al. Recombinant AAV2 transduction of primitive human hematopoietic stem cells capable of serial engraftment in immune-deficient mice. Proc Natl Acad Sci USA 2005; 102: 11053–11058.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Hargrove PW, Vanin EF, Kurtzman GJ, Nienhuis AW . High-level globin gene expression mediated by a recombinant adeno-associated virus genome that contains the 3′ γ globin gene regulatory element and integrates as tandem copies in erythroid cells. Blood 1997; 89: 2167–2175.

    CAS  PubMed  Google Scholar 

  48. Malik P, McQuiston SA, Yu XJ, Pepper KA, Krall WJ, Podsakoff GM et al. Recombinant adeno-associated virus mediates a high level of gene transfer but less efficient integration in the K562 human hematopoietic cell line. J Virol 1997; 71: 1776–1783.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Paz H, Wong CA, Li W, Santat L, Wong KK, Chatterjee S . Quiescent subpopulations of human CD34-positive hematopoietic stem cells are preferred targets for stable recombinant adeno-associated virus type 2 transduction. Hum Gene Ther 2007; 18: 614–626.

    CAS  PubMed  Google Scholar 

  50. Srivastava A . Adeno-associated virus-mediated gene transfer. J Cell Biochem 2008; 105: 17–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 2000; 288: 669–672.

    CAS  PubMed  Google Scholar 

  52. Kaiser J . Gene therapy. Seeking the cause of induced leukemias in X-SCID trial. Science 2003; 299: 495.

    CAS  PubMed  Google Scholar 

  53. Hacein-Bey-Abina S, von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003; 302: 415–419.

    CAS  PubMed  Google Scholar 

  54. Pike-Overzet K, de Ridder D, Weerkamp F, Baert MR, Verstegen MM, Brugman MH et al. Gene therapy: is IL2RG oncogenic in T-cell development? Nature 2006; 443: E5; discussion E6–7.

    PubMed  Google Scholar 

  55. Barabe F, Kennedy JA, Hope KJ, Dick JE . Modeling the initiation and progression of human acute leukemia in mice. Science 2007; 316: 600–604.

    CAS  PubMed  Google Scholar 

  56. Hanawa H, Persons DA, Nienhuis AW . Mobilization and mechanism of transcription of integrated self-inactivating lentiviral vectors. J Virol 2005; 79: 8410–8421.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Chang AH, Sadelain M . The genetic engineering of hematopoietic stem cells: the rise of lentiviral vectors, the conundrum of the ltr, and the promise of lineage-restricted vectors. Mol Ther 2007; 15: 445–456.

    CAS  PubMed  Google Scholar 

  58. Karlsson S, Ooka A, Woods NB . Development of gene therapy for blood disorders by gene transfer into haematopoietic stem cells. Haemophilia 2002; 8: 255–260.

    CAS  PubMed  Google Scholar 

  59. Kissler S, Stern P, Takahashi K, Hunter K, Peterson LB, Wicker LS . In vivo RNA interference demonstrates a role for Nramp1 in modifying susceptibility to type 1 diabetes. Nat Genet 2006; 38: 479–483.

    CAS  PubMed  Google Scholar 

  60. Marodon G, Mouly E, Blair EJ, Frisen C, Lemoine FM, Klatzmann D . Specific transgene expression in human and mouse CD4+ cells using lentiviral vectors with regulatory sequences from the CD4 gene. Blood 2003; 101: 3416–3423.

    CAS  PubMed  Google Scholar 

  61. Moreau T, Bardin F, Imbert J, Chabannon C, Tonnelle C . Restriction of transgene expression to the B-lymphoid progeny of human lentivirally transduced CD34+ cells. Mol Ther 2004; 10: 45–56.

    CAS  PubMed  Google Scholar 

  62. Moreau T, Barlogis V, Bardin F, Nunes JA, Calmels B, Chabannon C et al. Development of an enhanced B-specific lentiviral vector expressing BTK: a tool for gene therapy of XLA. Gene Ther 2008; 15: 942–952.

    CAS  PubMed  Google Scholar 

  63. Sather BD, Ryu BY, Stirling BV, Garibov M, Kerns HM, Humblet-Baron S et al. Development of B-lineage predominant lentiviral vectors for use in genetic therapies for B cell disorders. Mol Ther 2011; 19: 515–525.

    CAS  PubMed  Google Scholar 

  64. Cui Y, Golob J, Kelleher E, Ye Z, Pardoll D, Cheng L . Targeting transgene expression to antigen-presenting cells derived from lentivirus-transduced engrafting human hematopoietic stem/progenitor cells. Blood 2002; 99: 399–408.

    CAS  PubMed  Google Scholar 

  65. Shi Q, Wilcox DA, Morateck PA, Fahs SA, Kenny D, Montgomery RR . Targeting platelet GPIbalpha transgene expression to human megakaryocytes and forming a complete complex with endogenous GPIbβ and GPIX. J Thromb Haemost 2004; 2: 1989–1997.

    CAS  PubMed  Google Scholar 

  66. Kanaji S, Kuether EL, Fahs SA, Schroeder JA, Ware J, Montgomery RR et al. Correction of murine bernard-soulier syndrome by lentivirus-mediated gene therapy. Mol Ther 2011.

  67. Perumbeti A, Higashimoto T, Urbinati F, Franco R, Meiselman HJ, Witte D et al. A novel human γ-globin gene vector for genetic correction of sickle cell anemia in a humanized sickle mouse model: critical determinants for successful correction. Blood 2009; 114: 1174–1185.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Puthenveetil G, Scholes J, Carbonell D, Qureshi N, Xia P, Zeng L et al. Successful correction of the human β-thalassemia major phenotype using a lentiviral vector. Blood 2004; 104: 3445– 3453. 2004;

    CAS  PubMed  Google Scholar 

  69. Zhang F, Frost AR, Blundell MP, Bales O, Antoniou MN, Thrasher AJ . A ubiquitous chromatin opening element (UCOE) confers resistance to DNA methylation-mediated silencing of lentiviral vectors. Mol Ther 2010; 18: 1640–1649.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Leuci V, Gammaitoni L, Capellero S, Sangiolo D, Mesuraca M, Bond HM et al. Efficient transcriptional targeting of human hematopoietic stem cells and blood cell lineages by lentiviral vectors containing the regulatory element of the Wiskott–Aldrich syndrome gene. Stem Cells 2009; 27: 2815–2823.

    CAS  PubMed  Google Scholar 

  71. Levin MC, Lidberg U, Jirholt P, Adiels M, Wramstedt A, Gustafsson K et al. Evaluation of macrophage-specific promoters using lentiviral delivery in mice. Gene Ther; e-pub ahead of print 1 December 2011; doi: 10.1038/gt.2011.195.

    PubMed  PubMed Central  Google Scholar 

  72. O'Reilly D, Quinn CM, El-Shanawany T, Gordon S, Greaves DR . Multiple Ets factors and interferon regulatory factor-4 modulate CD68 expression in a cell type-specific manner. J Biol Chem 2003; 278: 21909–21919.

    CAS  PubMed  Google Scholar 

  73. Krowka JF, Sarin S, Namikawa R, McCune JM, Kaneshima H . Human T cells in the SCID-hu mouse are phenotypically normal and functionally competent. J Immunol 1991; 146: 3751–3756.

    CAS  PubMed  Google Scholar 

  74. McCune JM, Namikawa R, Kaneshima H, Shultz LD, Lieberman M, Weissman IL . The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science 1988; 241: 1632–1639.

    CAS  PubMed  Google Scholar 

  75. Dao MA, Pepper KA, Nolta JA . Long-term cytokine production from engineered primary human stromal cells influences human hematopoiesis in an in vivo xenograft model. Stem Cells 1997; 15: 443–454.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Kamel-Reid S, Dick JE . Engraftment of immune-deficient mice with human hematopoietic stem cells. Science 1988; 242: 1706–1709.

    CAS  PubMed  Google Scholar 

  77. Lapidot T, Pflumio F, Doedens M, Murdoch B, Williams DE, Dick JE . Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice. Science 1992; 255: 1137–1141.

    CAS  PubMed  Google Scholar 

  78. Vormoor J, Lapidot T, Pflumio F, Risdon G, Patterson B, Broxmeyer HE et al. Immature human cord blood progenitors engraft and proliferate to high levels in severe combined immunodeficient mice. Blood 1994; 83: 2489–2497.

    CAS  PubMed  Google Scholar 

  79. Larochelle A, Vormoor J, Hanenberg H, Wang JC, Bhatia M, Lapidot T et al. Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: implications for gene therapy. Nat Med 1996; 2: 1329–1337.

    CAS  PubMed  Google Scholar 

  80. Mazurier F, Fontanellas A, Salesse S, Taine L, Landriau S, Moreau-Gaudry F et al. A novel immunodeficient mouse model—RAG2 x common cytokine receptor γ chain double mutants—requiring exogenous cytokine administration for human hematopoietic stem cell engraftment. J Interferon Cytokine Res 1999; 19: 533–541.

    CAS  PubMed  Google Scholar 

  81. Kalberer CP, Siegler U, Wodnar-Filipowicz A . Human NK cell development in NOD/SCID mice receiving grafts of cord blood CD34+ cells. Blood 2003; 102: 127–135.

    CAS  PubMed  Google Scholar 

  82. Legrand N, Weijer K, Spits H . Experimental models to study development and function of the human immune system in vivo. J Immunol 2006; 176: 2053–2058.

    CAS  PubMed  Google Scholar 

  83. Carballido JM, Namikawa R, Carballido-Perrig N, Antonenko S, Roncarolo MG, de Vries JE . Generation of primary antigen-specific human T- and B-cell responses in immunocompetent SCID-hu mice. Nat Med 2000; 6: 103–106.

    CAS  PubMed  Google Scholar 

  84. Huntington ND, Legrand N, Alves NL, Jaron B, Weijer K, Plet A et al. IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J Exp Med 2009; 206: 25–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Wege AK, Ernst W, Eckl J, Frankenberger B, Vollmann-Zwerenz A, Mannel DN et al. Humanized tumor mice-A new model to study and manipulate the immune response in advanced cancer therapy. Int J Cancer; e-pub ahead of print 4 May 2011; doi:10.1002/ijc.26159.

    CAS  PubMed  Google Scholar 

  86. Pek EA, Chan T, Reid S, Ashkar AA . Characterization and IL-15 dependence of NK cells in humanized mice. Immunobiology 2011; 216: 218–224.

    CAS  PubMed  Google Scholar 

  87. van Lent AU, Dontje W, Nagasawa M, Siamari R, Bakker AQ, Pouw SM et al. IL-7 enhances thymic human T cell development in ‘human immune system’ Rag2−/−IL-2Rγc−/− mice without affecting peripheral T cell homeostasis. J Immunol 2009; 183: 7645–7655.

    CAS  PubMed  Google Scholar 

  88. Senpuku H, Asano T, Matin K, Salam MA, Tsuha Y, Horibata S et al. Effects of human interleukin-18 and interleukin-12 treatment on human lymphocyte engraftment in NOD-scid mouse. Immunology. 2002; 107: 232–242.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Huntington ND, Alves NL, Legrand N, Lim A, Strick-Marchand H, Mention JJ et al. IL-15 transpresentation promotes both human T-cell reconstitution and T-cell-dependent antibody responses in vivo. Proc Natl Acad Sci USA 2011; 108: 6217–6222.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Hu Z, van Rooijen N, Yang YG . Macrophages prevent human red blood cell reconstitution in immunodeficient mice. Blood 2011; 118: 5938–5946.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank Bettina Iliopoulou, Ryan Phennicie, Ed Browne and Peter Bak for their critical reading of the manuscript. This work was supported by funds from the Singapore-MIT Alliance for Research and Technology and the Ragon Institute of MGH, MIT and Harvard (to JC).

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Drake, A., Chen, Q. & Chen, J. Engineering humanized mice for improved hematopoietic reconstitution. Cell Mol Immunol 9, 215–224 (2012). https://doi.org/10.1038/cmi.2012.6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2012.6

Keywords

This article is cited by

Search

Quick links