Skip to main content

Mouse Genetic Background and Human Hematopoietic Stem Cells Biology; Tips for Humanization

  • Chapter
  • First Online:
Humanized Mice for HIV Research

Abstract

In past, many efforts have been made to develop immunodeficient mice that are permissive for human cell or tissue engraftment, and to model human hemato-lymphoid system (HHLS) for understanding human physiology and diseases. However, mouse environment remains suboptimal to robust maintenance of human hematopoietic stem cells (HSCs), and full development and function of human hematopoiesis and immunity. Thus, this limitation impedes long-term study of human immune function, especially in context of human immunodeficient virus (HIV) infection. Here, we summarize the recent findings on genetic and molecular determinants for efficient HHLS development in mice, and discuss how to improve humanization in order to sustain human hematopoiesis and enhance human immune function.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Yang Y-G, Sykes M. Xenotransplantation: current status and a perspective on the future. Nat Rev Immunol. 2007;7:519–31.

    CAS  PubMed  Google Scholar 

  2. Rongvaux A, Takizawa H, Strowig T, Willinger T, Eynon EE, Flavell RA, Manz MG. Human hemato-lymphoid system mice: current use and future potential for medicine. Annu Rev Immunol. 2013;31:635–74.

    PubMed Central  CAS  PubMed  Google Scholar 

  3. Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol. 2012;12:786–98.

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007;7:118–30.

    CAS  PubMed  Google Scholar 

  5. Legrand N, Weijer K, Spits H. Experimental models to study development and function of the human immune system in vivo. J Immunol. 2006;176:2053–8.

    CAS  PubMed  Google Scholar 

  6. Bosma GC, Custer RP, Bosma MJ. A severe combined immunodeficiency mutation in the mouse. Nature. 1983;301:527–30.

    CAS  PubMed  Google Scholar 

  7. Schuler W, Weiler IJ, Schuler A, Phillips RA, Rosenberg N, Mak TW, Kearney JF, Perry RP, Bosma MJ. Rearrangement of antigen receptor genes is defective in mice with severe combined immune deficiency. Cell. 1986;46:963–72.

    CAS  PubMed  Google Scholar 

  8. Malynn BA, Blackwell TK, Fulop GM, Rathbun GA, Furley AJ, Ferrier P, Heinke LB, Phillips RA, Yancopoulos GD, Alt FW. The Scid defect affects the final step of the immunoglobulin VDJ recombinase mechanism. Cell. 1988;54:453–60.

    CAS  PubMed  Google Scholar 

  9. Hesselton RM, Greiner DL, Mordes JP, Rajan TV, Sullivan JL, Shultz LD. High levels of human peripheral blood mononuclear cell engraftment and enhanced susceptibility to human immunodeficiency virus type 1 infection in NOD/LtSz-Scid/Scid mice. J Infect Dis. 1995;172:974–82.

    CAS  PubMed  Google Scholar 

  10. DiSanto JP, Müller W, Guy-Grand D, Fischer A, Rajewsky K. Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proc Natl Acad Sci U S A. 1995;92:377–81.

    PubMed Central  CAS  PubMed  Google Scholar 

  11. Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL, Russell SM, Drago J, Noguchi M, Grinberg A, Bloom ET. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity. 1995;2:223–38.

    CAS  PubMed  Google Scholar 

  12. Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V, Mendelsohn M, Charron J, Datta M, Young F, Stall AM. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992;68:855–67.

    CAS  PubMed  Google Scholar 

  13. Ito M, Hiramatsu H, Kobayashi K, et al. NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood. 2002;100:3175–82.

    CAS  PubMed  Google Scholar 

  14. Shultz LD, Lyons BL, Burzenski LM, et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol. 2005;174:6477–89.

    CAS  PubMed  Google Scholar 

  15. Mazurier F, Fontanellas A, Salesse S, Taine L, Landriau S, Moreau-Gaudry F, Reiffers J, Peault B, Di Santo JP, de Verneuil H. A novel immunodeficient mouse model–RAG2 x common cytokine receptor gamma chain double mutants–requiring exogenous cytokine administration for human hematopoietic stem cell engraftment. J Interferon Cytokine Res. 1999;19:533–41.

    CAS  PubMed  Google Scholar 

  16. Greiner DL, Hesselton RA, Shultz LD. SCID mouse models of human stem cell engraftment. Stem Cells. 1998;16:166–77.

    CAS  PubMed  Google Scholar 

  17. Brehm MA, Cuthbert A, Yang C, et al. Parameters for establishing humanized mouse models to study human immunity: analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2rgamma(null) mutation. Clin Immunol. 2010;135:84–98.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Takenaka K, Prasolava TK, Wang JCY, Mortin-Toth SM, Khalouei S, Gan OI, Dick JE, Danska JS. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat Immunol. 2007;8:1313–23.

    CAS  PubMed  Google Scholar 

  19. Yamauchi T, Takenaka K, Urata S, et al. Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment. Blood. 2013;121:1316–25.

    CAS  PubMed  Google Scholar 

  20. Mercier FE, Ragu C, Scadden DT. The bone marrow at the crossroads of blood and immunity. Nat Rev Immunol. 2012;12:49–60.

    CAS  Google Scholar 

  21. Manz MG. Human-hemato-lymphoid-system mice: opportunities and challenges. Immunity. 2007;26:537–41.

    CAS  PubMed  Google Scholar 

  22. Rongvaux A, Willinger T, Takizawa H, et al. Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo. Proc Natl Acad Sci U S A. 2011;108:2378–83.

    PubMed Central  CAS  PubMed  Google Scholar 

  23. Willinger T, Rongvaux A, Takizawa H, 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 U S A. 2011;108:2390–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Rathinam C, Poueymirou WT, Rojas J, Murphy AJ, Valenzuela DM, Yancopoulos GD, Rongvaux A, Eynon EE, Manz MG, Flavell RA. Efficient differentiation and function of human macrophages in humanized CSF-1 mice. Blood. 2011;118:3119–28.

    CAS  PubMed  Google Scholar 

  25. Rongvaux A, Willinger T, Martinek J, et al. Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol. 2014;32:364–372.

    Google Scholar 

  26. Strowig T, Rongvaux A, Rathinam C, Takizawa H, Borsotti C, Philbrick W, Eynon EE, Manz MG, Flavell RA. Transgenic expression of human signal regulatory protein alpha in Rag2-/- gamma(c)-/- mice improves engraftment of human hematopoietic cells in humanized mice. Proc Natl Acad Sci USA. 2011;108:13218–13223.

    Google Scholar 

  27. Baum CM, Weissman IL, Tsukamoto AS, Buckle AM, Peault B. Isolation of a candidate human hematopoietic stem-cell population. Proc Natl Acad Sci U S A. 1992;89:2804–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Craig W, Kay R, Cutler RL, Lansdorp PM. Expression of Thy-1 on human hematopoietic progenitor cells. J Exp Med. 1993;177:1331–42.

    CAS  PubMed  Google Scholar 

  29. Kondo M, Wagers AJ, Manz MG, Prohaska SS, Scherer DC, Beilhack GF, Shizuru JA, Weissman IL. Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu Rev Immunol. 2003;21:759–806.

    CAS  PubMed  Google Scholar 

  30. Larochelle A, Vormoor J, Hanenberg H, et al. Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: implications for gene therapy. Nat Med. 1996;2:1329–37.

    CAS  PubMed  Google Scholar 

  31. Bhatia M, Wang JC, Kapp U, Bonnet D, Dick JE. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci U S A. 1997;94:5320–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Majeti R, Park CY, Weissman IL. Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood. Cell Stem Cell. 2007;1:635–45.

    PubMed Central  CAS  PubMed  Google Scholar 

  33. McKenzie JL, Takenaka K, Gan OI, Doedens M, Dick JE. Low rhodamine 123 retention identifies long-term human hematopoietic stem cells within the Lin-CD34+CD38− population. Blood. 2007;109:543–5.

    CAS  PubMed  Google Scholar 

  34. 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 

  35. Allsopp RC, Morin GB, DePinho R, Harley CB, Weissman IL. Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood. 2003;102:517–20.

    CAS  PubMed  Google Scholar 

  36. Zhang J, Niu C, Ye L, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003;425:836–41.

    CAS  PubMed  Google Scholar 

  37. Calvi LM, Adams GB, Weibrecht KW, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425:841–6.

    CAS  PubMed  Google Scholar 

  38. Mansour A, Abou-Ezzi G, Sitnicka E, Jacobsen SEW, Wakkach A, Blin-Wakkach C. Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow. J Exp Med. 2012;209:537–49.

    PubMed Central  CAS  PubMed  Google Scholar 

  39. Ding L, Morrison SJ. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature. 2013;495:231–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009;460:259–63.

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Yamazaki S, Ema H, Karlsson G, Yamaguchi T, Miyoshi H, Shioda S, Taketo MM, Karlsson S, Iwama A, Nakauchi H. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell. 2011;147:1146–58.

    CAS  PubMed  Google Scholar 

  42. Chow A, Lucas D, Hidalgo A, et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med. 2011;208:261–71.

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Winkler IG, Sims NA, Pettit AR, et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood. 2010;116:4815–28.

    CAS  PubMed  Google Scholar 

  44. Omatsu Y, Sugiyama T, Kohara H, Kondoh G, Fujii N, Kohno K, Nagasawa T. The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity. 2010;33:387–99.

    CAS  PubMed  Google Scholar 

  45. Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012;481:457–62.

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Méndez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, Scadden DT, Ma’ayan A, Enikolopov GN, Frenette PS. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466:829–34.

    PubMed Central  PubMed  Google Scholar 

  47. Morikawa S, Mabuchi Y, Kubota Y, et al. Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. J Exp Med. 2009;206:2483–96.

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, Ito K, Koh GY, Suda T. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118:149–61.

    CAS  PubMed  Google Scholar 

  49. Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25:977–88.

    CAS  PubMed  Google Scholar 

  50. Greenbaum A, Hsu Y-MS, Day RB, Schuettpelz LG, Christopher MJ, Borgerding JN, Nagasawa T, Link DC. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature. 2013;495:227–30.

    PubMed Central  CAS  PubMed  Google Scholar 

  51. Yoshihara H, Arai F, Hosokawa K, et al. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell. 2007;1:685–97.

    CAS  PubMed  Google Scholar 

  52. Qian H, Buza-Vidas N, Hyland CD, Jensen CT, Antonchuk J, Månsson R, Thoren LA, Ekblom M, Alexander WS, Jacobsen SEW. Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. Cell Stem Cell. 2007;1:671–84.

    CAS  PubMed  Google Scholar 

  53. Butler JM, Nolan DJ, Vertes EL, et al. Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell. 2010;6:251–64.

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Sugimura R, He XC, Venkatraman A, et al. Noncanonical Wnt signaling maintains hematopoietic stem cells in the niche. Cell. 2012;150:351–65.

    CAS  PubMed  Google Scholar 

  55. Hosokawa K, Arai F, Yoshihara H, et al. Cadherin-based adhesion is a potential target for niche manipulation to protect hematopoietic stem cells in adult bone marrow. Cell Stem Cell. 2010;6:194–8.

    CAS  PubMed  Google Scholar 

  56. Winkler IG, Barbier V, Nowlan B, Jacobsen RN, Forristal CE, Patton JT, Magnani JL, Lévesque J-P. Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance. Nat Med. 2012;18:1651–7.

    CAS  PubMed  Google Scholar 

  57. Sacchetti B, Funari A, Michienzi S, et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell. 2007;131:324–36.

    CAS  PubMed  Google Scholar 

  58. 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;241:1632–9.

    CAS  PubMed  Google Scholar 

  59. Mosier DE, Gulizia RJ, Baird SM, Wilson DB. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature. 1988;335:256–9.

    CAS  PubMed  Google Scholar 

  60. Fulop GM, Phillips RA. The scid mutation in mice causes a general defect in DNA repair. Nature. 1990;347:479–82.

    CAS  PubMed  Google Scholar 

  61. Danska JS, Pflumio F, Williams CJ, Huner O, Dick JE, Guidos CJ. Rescue of T cell-specific V(D)J recombination in SCID mice by DNA-damaging agents. Science. 1994;266:450–55.

    CAS  PubMed  Google Scholar 

  62. Bosma GC, Fried M, Custer RP, Carroll A, Gibson DM, Bosma MJ. Evidence of functional lymphocytes in some (leaky) Scid mice. J Exp Med. 1988;167:1016–33.

    CAS  PubMed  Google Scholar 

  63. Nonoyama S, Smith FO, Ochs HD. Specific antibody production to a recall or a neoantigen by SCID mice reconstituted with human peripheral blood lymphocytes. J Immunol. 1993;151:3894–901.

    CAS  PubMed  Google Scholar 

  64. Shultz LD, Schweitzer PA, Christianson SW, Gott B, Schweitzer IB, Tennent B, McKenna S, Mobraaten L, Rajan TV, Greiner DL. Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol. 1995;154:180–91.

    CAS  PubMed  Google Scholar 

  65. Qing Y, Lin Y, Gerson SL. An intrinsic BM hematopoietic niche occupancy defect of HSC in scid mice facilitates exogenous HSC engraftment. Blood. 2012;119:1768–71.

    PubMed Central  CAS  PubMed  Google Scholar 

  66. Zhang S, Yajima H, Huynh H, et al. Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair. J Cell Biol. 2011;193:295–305.

    PubMed Central  CAS  PubMed  Google Scholar 

  67. Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. 2007;447:725–9.

    CAS  PubMed  Google Scholar 

  68. Nijnik A, Woodbine L, Marchetti C, et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature. 2007;447:686–90.

    CAS  PubMed  Google Scholar 

  69. Mohrin M, Bourke E, Alexander D, Warr MR, Barry-Holson K, Le Beau MM, Morrison CG, Passegué E. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell. 2010;7:174–85.

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Serreze DV, Leiter EH. Defective activation of T suppressor cell function in nonobese diabetic mice. Potential relation to cytokine deficiencies. J Immunol. 1988;140:3801–7.

    CAS  PubMed  Google Scholar 

  71. Baxter AG, Cooke A. Complement lytic activity has no role in the pathogenesis of autoimmune diabetes in NOD mice. Diabetes. 1993;42:1574–8.

    CAS  PubMed  Google Scholar 

  72. Tanaka T, Kitamura F, Nagasaka Y, Kuida K, Suwa H, Miyasaka M. Selective long-term elimination of natural killer cells in vivo by an anti-interleukin 2 receptor beta chain monoclonal antibody in mice. J Exp Med. 1993;178:1103–7.

    CAS  PubMed  Google Scholar 

  73. McKenzie JL, Gan OI, Doedens M, Dick JE. Human short-term repopulating stem cells are efficiently detected following intrafemoral transplantation into NOD/SCID recipients depleted of CD122+ cells. Blood. 2005;106:1259–61.

    CAS  PubMed  Google Scholar 

  74. 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 

  75. Barclay AN, Brown MH. The SIRP family of receptors and immune regulation. Nat Rev Immunol. 2006;6:457–64.

    CAS  PubMed  Google Scholar 

  76. Matozaki T, Murata Y, Okazawa H, Ohnishi H. Functions and molecular mechanisms of the CD47-SIRPalpha signalling pathway. Trends Cell Biol. 2009;19:72–80.

    CAS  PubMed  Google Scholar 

  77. Legrand N, Huntington ND, Nagasawa M, et al. Functional CD47/signal regulatory protein alpha (SIRP(alpha)) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo. Proc Natl Acad Sci USA. 2011;108:13224–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Strowig T, Rongvaux A, Rathinam C, Takizawa H, Borsotti C, Philbrick W, Eynon EE, Manz MG, Flavell RA. Transgenic expression of human signal regulatory protein alpha in Rag2–/–gamma(c)–/– mice improves engraftment of human hematopoietic cells in humanized mice. Proc Natl Acad Sci U S A. 2011;108:13218–23.

    PubMed Central  CAS  PubMed  Google Scholar 

  79. Terpstra W, Leenen PJ, van den Bos C, et al. Facilitated engraftment of human hematopoietic cells in severe combined immunodeficient mice following a single injection of Cl2MDP liposomes. Leukemia. 1997;11:1049–54.

    CAS  PubMed  Google Scholar 

  80. Rozemuller H, Knaän-Shanzer S, Hagenbeek A, van Bloois L, Storm G, Martens ACM. Enhanced engraftment of human cells in RAG2/gammac double-knockout mice after treatment with CL2MDP liposomes. Exp Hematol. 2004;32:1118–25.

    CAS  PubMed  Google Scholar 

  81. Christianson SW, Shultz LD, Leiter EH. Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Diabetes. 1993;42:44–55.

    CAS  PubMed  Google Scholar 

  82. Prochazka M, Gaskins HR, Shultz LD, Leiter EH. The nonobese diabetic scid mouse: model for spontaneous thymomagenesis associated with immunodeficiency. Proc Natl Acad Sci U S A. 1992;89:3290–94.

    PubMed Central  CAS  PubMed  Google Scholar 

  83. Yahata T, Ando K, Nakamura Y, Ueyama Y, Shimamura K, Tamaoki N, Kato S, Hotta T. Functional human T lymphocyte development from cord blood CD34+ cells in nonobese diabetic/Shi-scid, IL-2 receptor gamma null mice. J Immunol. 2002;169:204–9.

    CAS  PubMed  Google Scholar 

  84. Hiramatsu H, Nishikomori R, Heike T, Ito M, Kobayashi K, Katamura K, Nakahata T. Complete reconstitution of human lymphocytes from cord blood CD34+ cells using the NOD/SCID/gammacnull mice model. Blood. 2003;102:873–80.

    CAS  PubMed  Google Scholar 

  85. Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G, Watanabe T, Akashi K, Shultz LD, Harada M. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice. Blood. 2005;106:1565–73.

    PubMed Central  CAS  PubMed  Google Scholar 

  86. Berland R, Wortis HH. Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol. 2002;20:253–300.

    CAS  PubMed  Google Scholar 

  87. Becker PD, Legrand N, van Geelen CMM, et al. Generation of human antigen-specific monoclonal IgM antibodies using vaccinated “human immune system” mice. PLoS ONE. 2010;5(10):e13137. doi:10.1371/journal.pone.0013137.

    Google Scholar 

  88. Ippolito GC, Hoi KH, Reddy ST, et al. Antibody repertoires in humanized NOD-scid-IL2Rγ(null) mice and human B cells reveals human-like diversification and tolerance checkpoints in the mouse. PLoS ONE. 2012;7:e35497.

    PubMed Central  CAS  PubMed  Google Scholar 

  89. Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti J-C, Lanzavecchia A, Manz MG. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science. 2004;304:104–7.

    CAS  PubMed  Google Scholar 

  90. van Rijn RS, Simonetti.ER, Hagenbeek A, et al. A new xenograft model for graft-versus-host disease by intravenous transfer of human peripheral blood mononuclear cells in RAG2−/− gammac−/− double-mutant mice. Blood. 2003;102:2522–31.

    PubMed  Google Scholar 

  91. Neagu MR, Ziegler P, Pertel T, Strambio-De-Castillia C, Grütter C, Martinetti G, Mazzucchelli L, Grütter M, Manz MG, Luban J. Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components. J Clin Invest. 2009;119:3035–47.

    PubMed Central  CAS  PubMed  Google Scholar 

  92. Tjønnfjord GE, Steen R, Veiby OP, Friedrich W, Egeland T. Evidence for engraftment of donor-type multipotent CD34+ cells in a patient with selective T-lymphocyte reconstitution after bone marrow transplantation for B-SCID. Blood. 1994;84:3584–89.

    PubMed  Google Scholar 

  93. Coulombel L. Identification of hematopoietic stem/progenitor cells: strength and drawbacks of functional assays. Oncogene. 2004;23:7210–22.

    CAS  PubMed  Google Scholar 

  94. Matsumura T, Kametani Y, Ando K, et al. Functional CD5+ B cells develop predominantly in the spleen of NOD/SCID/gammac(null) (NOG) mice transplanted either with human umbilical cord blood, bone marrow, or mobilized peripheral blood CD34+ cells. Exp Hematol. 2003;31:789–97.

    PubMed  Google Scholar 

  95. Kerre TCC, De Smet G, De Smedt M, Zippelius A, Pittet MJ, Langerak AW, De Bosscher J, Offner F, Vandekerckhove B, Plum J. Adapted NOD/SCID model supports development of phenotypically and functionally mature T cells from human umbilical cord blood CD34(+) cells. Blood. 2002;99:1620–26.

    CAS  PubMed  Google Scholar 

  96. Holt N, Wang J, Kim K, et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat Biotechnol. 2010;28:839–47.

    PubMed Central  CAS  PubMed  Google Scholar 

  97. Gimeno R, Weijer K, Voordouw A, Uittenbogaart CH, Legrand N, Alves NL, Wijnands E, Blom B, Spits H. Monitoring the effect of gene silencing by RNA interference in human CD34+ cells injected into newborn RAG2−/− gammac−/− mice: functional inactivation of p53 in developing T cells. Blood. 2004;104:3886–93.

    CAS  PubMed  Google Scholar 

  98. Notta F, Doulatov S, Dick JE. Engraftment of human hematopoietic stem cells is more efficient in female NOD/SCID/IL-2Rgc-null recipients. Blood. 2010;115:3704–07.

    CAS  PubMed  Google Scholar 

  99. Tavor S, Petit I, Porozov S, Goichberg P, Avigdor A, Sagiv S, Nagler A, Naparstek E, Lapidot T. Motility, proliferation, and egress to the circulation of human AML cells are elastase dependent in NOD/SCID chimeric mice. Blood. 2005;106:2120–27.

    CAS  PubMed  Google Scholar 

  100. Yahata T, Ando K, Sato T, Miyatake H, Nakamura Y, Muguruma Y, Kato S, Hotta T. A highly sensitive strategy for SCID-repopulating cell assay by direct injection of primitive human hematopoietic cells into NOD/SCID mice bone marrow. Blood. 2003;101:2905–13.

    CAS  PubMed  Google Scholar 

  101. Mazurier F, Doedens M, Gan OI, Dick JE. Rapid myeloerythroid repopulation after intrafemoral transplantation of NOD-SCID mice reveals a new class of human stem cells. Nat Med. 2003;9:959–63.

    CAS  PubMed  Google Scholar 

  102. Chabner KT, Adams GB, Qiu J, Moskowitz M, Marsters ES, Topulos GP, Scadden DT. Direct vascular delivery of primitive hematopoietic cells to bone marrow improves localization but not engraftment. Blood. 2004;103:4685–86.

    CAS  PubMed  Google Scholar 

  103. Volk A, Hartmann S, Muik A, Geiss Y, Königs C, Dietrich U, Laer von D, Kimpel J. Comparison of three humanized mouse models for adoptive T cell transfer. J Gene Med. 2012;14:540–48.

    CAS  PubMed  Google Scholar 

  104. Hayakawa J, Hsieh MM, Uchida N, Phang O, Tisdale JF. Busulfan produces efficient human cell engraftment in NOD/LtSz-Scid IL2Rgamma(null) mice. Stem Cells. 2009;27:175–82.

    PubMed Central  CAS  PubMed  Google Scholar 

  105. Singh M, Singh P, Gaudray G, et al. An improved protocol for efficient engraftment in NOD/LTSZ-SCIDIL-2Rγnull mice allows HIV replication and development of anti-HIV immune responses. PLoS ONE. 2012;7:e38491.

    PubMed Central  CAS  PubMed  Google Scholar 

  106. Czechowicz A, Kraft D, Weissman IL, Bhattacharya D. Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches. Science. 2007;318:1296–99.

    PubMed Central  CAS  PubMed  Google Scholar 

  107. Takizawa H, Schanz U, Manz MG. Ex vivo expansion of hematopoietic stem cells: mission accomplished? Swiss Med Wkly. 2011;141:w13316.

    PubMed  Google Scholar 

  108. Dzierzak E, Speck NA. Of lineage and legacy: the development of mammalian hematopoietic stem cells. Nat Immunol. 2008;9:129–36.

    PubMed Central  CAS  PubMed  Google Scholar 

  109. Cumano A, Godin I. Ontogeny of the hematopoietic system. Annu Rev Immunol. 2007;25:745–85.

    CAS  PubMed  Google Scholar 

  110. Kennedy M, Awong G, Sturgeon CM, Ditadi A, LaMotte-Mohs R, Zúñiga-Pflücker JC, Keller G. T lymphocyte potential marks the emergence of definitive hematopoietic progenitors in human pluripotent stem cell differentiation cultures. Cell Rep. 2012;2:1722–35.

    CAS  PubMed  Google Scholar 

  111. Choi K-D, Vodyanik MA, Togarrati PP, et al. Identification of the hemogenic endothelial progenitor and its direct precursor in human pluripotent stem cell differentiation cultures. Cell Rep. 2012;2:553–67.

    PubMed Central  CAS  PubMed  Google Scholar 

  112. Amabile G, Welner RS, Nombela-Arrieta C, et al. In vivo generation of transplantable human hematopoietic cells from induced pluripotent stem cells. Blood. 2013;121:1255–64.

    PubMed Central  CAS  PubMed  Google Scholar 

  113. Pereira C-F, Chang B, Qiu J, et al. Induction of a hemogenic program in mouse fibroblasts. Cell Stem Cell. 2013;13:205–18.

    PubMed Central  CAS  PubMed  Google Scholar 

  114. Szabo E, Rampalli S, Risueño RM, Schnerch A, Mitchell R, Fiebig-Comyn A, Levadoux-Martin M, Bhatia M. Direct conversion of human fibroblasts to multilineage blood progenitors. Nature. 2010;468:521–26.

    CAS  PubMed  Google Scholar 

  115. Doulatov S, Vo LT, Chou SS, et al. Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors. Cell Stem Cell. 2013;13:459–70.

    CAS  PubMed  Google Scholar 

  116. Melkus MW, Estes JD, Padgett-Thomas A, Gatlin J, Denton PW, Othieno FA, Wege AK, Haase AT, Garcia JV. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med. 2006;12:1316–22.

    CAS  PubMed  Google Scholar 

  117. Akkina R. New generation humanized mice for virus research: comparative aspects and future prospects. Virology. 2013;435:14–28.

    PubMed Central  CAS  PubMed  Google Scholar 

  118. Lee J, Li M, Milwid J, et al. Implantable microenvironments to attract hematopoietic stem/cancer cells. Proc Natl Acad Sci U S A. 2012;109:19638–43.

    PubMed Central  CAS  PubMed  Google Scholar 

  119. Scotti C, Piccinini E, Takizawa H, Todorov A, Bourgine P, Papadimitropoulos A, Barbero A, Manz MG, Martin I. Engineering of a functional bone organ through endochondral ossification. Proc Natl Acad Sci U S A. 2013;110:3997–4002.

    PubMed Central  CAS  PubMed  Google Scholar 

  120. Drake AC, Chen Q, Chen J. Engineering humanized mice for improved hematopoietic reconstitution. Cell Mol Immunol. 2012;9:215–24.

    PubMed Central  CAS  PubMed  Google Scholar 

  121. Brehm MA, Racki WJ, Leif J, et al. Engraftment of human HSCs in nonirradiated newborn NOD-scid IL2rγ null mice is enhanced by transgenic expression of membrane-bound human SCF. Blood. 2012;119:2778–88.

    PubMed Central  CAS  PubMed  Google Scholar 

  122. Danner R, Chaudhari SN, Rosenberger J, Surls J, Richie TL, Brumeanu T-D, Casares S. 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.

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Strowig T, Gurer C, Ploss A, et al. Priming of protective T cell responses against virus-induced tumors in mice with human immune system components. J Exp Med. 2009;206:1423–34.

    PubMed Central  PubMed  Google Scholar 

  124. Shultz LD, Saito Y, Najima Y, et al. Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice. Proc Natl Acad Sci U S A. 2010;107:13022–27.

    PubMed Central  CAS  PubMed  Google Scholar 

  125. Takagi S, Saito Y, Hijikata A, et al. Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation. Blood. 2012;119:2768–77.

    PubMed Central  CAS  PubMed  Google Scholar 

  126. Lan P, Tonomura N, Shimizu A, Wang S, Yang Y-G. Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation. Blood. 2006;108:487–92.

    CAS  PubMed  Google Scholar 

  127. Kumar P, Ban H-S, Kim S-S, et al. T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell. 2008;134:577–86.

    PubMed Central  CAS  PubMed  Google Scholar 

  128. 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 IL2Rγ(null) humanized mice. Blood. 2011;117:3076–86.

    PubMed Central  CAS  PubMed  Google Scholar 

  129. Suzuki M, Takahashi T, Katano I, Ito R, Ito M, Harigae H, Ishii N, Sugamura K. Induction of human humoral immune responses in a novel HLA-DR-expressing transgenic NOD/Shi-scid/γcnull mouse. Int Immunol. 2012;24:243–52.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hitoshi Takizawa .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Kovtonyuk, L., Takizawa, H. (2014). Mouse Genetic Background and Human Hematopoietic Stem Cells Biology; Tips for Humanization. In: Poluektova, L., Garcia, J., Koyanagi, Y., Manz, M., Tager, A. (eds) Humanized Mice for HIV Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1655-9_4

Download citation

Publish with us

Policies and ethics