Hematopoietic stem cells (HSCs) represent one of the first amenable experimental models that enhanced our understanding of stem cell behavior. Features of the hematopoietic system facilitating the early development of this experimental model include the fact that the hematopoietic system is a naturally regenerative organ comprising cells that are migratory in nature. The fact that a few or even single cells could be demonstrated to regenerate the entire hematopoietic system in an irradiated recipient made it possible to perform retrospective identification of the engrafting cell and the fate of its progeny. In addition, clinical interests such as gene therapy and regenerative medicine have driven research to understand the pathways that maintain and modify stem cell behavior in vitro and in vivo. This chapter reviews a selection of cell surface receptors, intracellular signaling molecules, regulators of cell death and proliferation, and transcriptional regulators that are known to play an important role in maintaining HSCs in the adult. A large number of mouse knockout studies have been performed that provide a framework of pathways that are essential for the maintenance of steady-state hematopoiesis and for maintenance in conditions in which the hematopoietic system must regenerate. To understand how manipulating these pathways affects stem cell function, the phenotypic and functional characterization of murine and human HSCs has been refined over time to include different mouse strains and conditions, including specific knockout animals. In turn, the analysis of loss- and gain-of-function models has enriched our understanding of the stability of HSC identity.


Hematopoietic Stem Cell Hematopoietic System Cell Stem Cell Human Hematopoietic Stem Cell Signaling Lymphocytic Activation Molecule 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abkowitz, J. L., and Chen, J. (2007). Studies of c-Mpl function distinguish the replication of hematopoietic stem cells from the expansion of differentiating clones. Blood 109, 5186–5190.PubMedGoogle Scholar
  2. Adolfsson, J., Borge, O. J., Bryder, D., Theilgaard-Monch, K., Astrand-Grundstrom, I., Sitnicka, E., Sasaki, Y., and Jacobsen, S. E. (2001). Upregulation of Flt3 expression within the bone marrow Lin — Sca1 + c-kit + stem cell compartment is accompanied by loss of self-renewal capacity. Immunity 15, 659–669.PubMedGoogle Scholar
  3. Antonchuk, J., Sauvageau, G., and Humphries, R. K. (2002). HOXB4-induced expansion of adult hematopoietic stem cells ex vivo. Cell 109, 39–45.PubMedGoogle Scholar
  4. Arai, F., Hirao, A., Ohmura, M., Sato, H., Matsuoka, S., Takubo, K., Ito, K., Koh, G. Y., and Suda, T. (2004). Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161.PubMedGoogle Scholar
  5. Baena, E., Ortiz, M., Martinez, A. C., and de Alboran, I. M. (2007). c-Myc is essential for hemat-opoietic stem cell differentiation and regulates Lin — Sca-1 + c-Kit — cell generation through p21. Exp Hematol 35, 1333–1343.PubMedGoogle Scholar
  6. Bertoncello, I., Hodgson, G. S., and Bradley, T. R. (1985). Multiparameter analysis of transplant-able hemopoietic stem cells. I. The separation and enrichment of stem cells homing to marrow and spleen on the basis of rhodamine-123 fluorescence. Exp Hematol 13, 999–1006.Google Scholar
  7. Besmer, P., Murphy, J. E., George, P. C., Qiu, F. H., Bergold, P. J., Lederman, L., Snyder, H. W., Jr., Brodeur, D., Zuckerman, E. E., and Hardy, W. D. (1986). A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family. Nature 320, 415–421.PubMedGoogle Scholar
  8. Biermann, K., Goke, F., Nettersheim, D., Eckert, D., Zhou, H., Kahl, P., Gashaw, I., Schorle, H., and Buttner, R. (2007). c-KIT is frequently mutated in bilateral germ cell tumours and down-regulated during progression from intratubular germ cell neoplasia to seminoma. J Pathol 213, 311–318.PubMedGoogle Scholar
  9. Branda, C. S., and Dymecki, S. M. (2004). Talking about a revolution: the impact of site-specific recombinases on genetic analyses in mice. Dev Cell 6, 7–28.PubMedGoogle Scholar
  10. Broudy, V. C. (1997). Stem cell factor and hematopoiesis. Blood 90, 1345–1364.PubMedGoogle Scholar
  11. Bryder, D., Ramsfjell, V., Dybedal, I., Theilgaard-Monch, K., Hogerkorp, C. M., Adolfsson, J., Borge, O. J., and Jacobsen, S. E. (2001). Self-renewal of multipotent long-term repopulating hematopoietic stem cells is negatively regulated by Fas and tumor necrosis factor receptor activation. J Exp Med 194, 941–952.PubMedGoogle Scholar
  12. Buske, C., and Humphries, R. K. (2000). Homeobox genes in leukemogenesis. Int J Hematol 71, 301–308.PubMedGoogle Scholar
  13. Cadigan, K. M., and Nusse, R. (1997). Wnt signaling: a common theme in animal development. Genes Dev 11, 3286–3305.PubMedGoogle Scholar
  14. Cancelas, J. A., Jansen, M., and Williams, D. A. (2006). The role of chemokine activation of Rac GTPases in hematopoietic stem cell marrow homing, retention, and peripheral mobilization. Exp Hematol 34, 976–985.PubMedGoogle Scholar
  15. Carpinelli, M. R., Hilton, D. J., Metcalf, D., Antonchuk, J. L., Hyland, C. D., Mifsud, S. L., Di Rago, L., Hilton, A. A., Willson, T. A., Roberts, A. W., et-al. (2004). Suppressor screen in Mpl —/— mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling. Proc Natl Acad Sci USA 101, 6553–6558.PubMedGoogle Scholar
  16. Cavalli, G. (2002). Chromatin as a eukaryotic template of genetic information. Curr Opin Cell Biol 14, 269–278.PubMedGoogle Scholar
  17. Chabot, B., Stephenson, D. A., Chapman, V. M., Besmer, P., and Bernstein, A. (1988). The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus. Nature 335, 88–89.PubMedGoogle Scholar
  18. Cheng, T., Rodrigues, N., Shen, H., Yang, Y., Dombkowski, D., Sykes, M., and Scadden, D. T. (2000). Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287, 1804–1808.PubMedGoogle Scholar
  19. Christensen, J. L., and Weissman, I. L. (2001). Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc Natl Acad Sci USA 98, 14541–14546.PubMedGoogle Scholar
  20. Core, N., Bel, S., Gaunt, S. J., Aurrand-Lions, M., Pearce, J., Fisher, A., and Djabali, M. (1997). Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice. Development 124, 721–729.PubMedGoogle Scholar
  21. Czechowicz, A., Kraft, D., Weissman, I. L., and Bhattacharya, D. (2007). Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches. Science 318, 1296–1299.PubMedGoogle Scholar
  22. Domen, J., and Weissman, I. L. (2000). Hematopoietic stem cells need two signals to prevent apoptosis; BCL-2 can provide one of these, Kitl/c-Kit signaling the other. J Exp Med 192, 1707–1718.PubMedGoogle Scholar
  23. Dykstra, B., Ramunas, J., Kent, D., McCaffrey, L., Szumsky, E., Kelly, L., Farn, K., Blaylock, A., Eaves, C., and Jervis, E. (2006). High-resolution video monitoring of hematopoietic stem cells cultured in single-cell arrays identifies new features of self-renewal. Proc Natl Acad Sci USA 103, 8185–8190.PubMedGoogle Scholar
  24. Dzierzak, E., and Speck, N. A. (2008). Of lineage and legacy: the development of mammalian hematopoietic stem cells. Nat Immunol 9, 129–136.PubMedGoogle Scholar
  25. Eaves, C. J., Sutherland, H. J., Udomsakdi, C., Lansdorp, P. M., Szilvassy, S. J., Fraser, C. C., Humphries, R. K., Barnett, M. J., Phillips, G. L., and Eaves, A. C. (1992). The human hematopoietic stem cell in vitro and in vivo. Blood Cells 18, 301–307.PubMedGoogle Scholar
  26. Goodell, M. A., Brose, K., Paradis, G., Conner, A. S., and Mulligan, R. C. (1996). Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 183, 1797–1806.PubMedGoogle Scholar
  27. Greil, R., Anether, G., Johrer, K., and Tinhofer, I. (2003). Tuning the rheostat of the myelopoietic system via Fas and TRAIL. Crit Rev Immunol 23, 301–322.PubMedGoogle Scholar
  28. Grisendi, S., and Pandolfi, P. P. (2005). Two decades of cancer genetics: from specificity to pleiotropic networks. Cold Spring Harb Symp Quant Biol 70, 83–91.PubMedGoogle Scholar
  29. Growney, J. D., Shigematsu, H., Li, Z., Lee, B. H., Adelsperger, J., Rowan, R., Curley, D. P., Kutok, J. L., Akashi, K., Williams, I. R., et-al. (2005). Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. Blood 106, 494–504.PubMedGoogle Scholar
  30. Guenechea, G., Gan, O. I., Dorrell, C., and Dick, J. E. (2001). Distinct classes of human stem cells that differ in proliferative and self-renewal potential. Nat Immunol 2, 75–82.PubMedGoogle Scholar
  31. Harada, N., Tamai, Y., Ishikawa, T., Sauer, B., Takaku, K., Oshima, M., and Taketo, M. M. (1999). Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene. EMBO J 18, 5931–5942.PubMedGoogle Scholar
  32. Hariharan, I. K., and Haber, D. A. (2003). Yeast, flies, worms, and fish in the study of human disease. N Engl J Med 348, 2457–2463.PubMedGoogle Scholar
  33. Heissig, B., Hattori, K., Dias, S., Friedrich, M., Ferris, B., Hackett, N. R., Crystal, R. G., Besmer, P., Lyden, D., Moore, M. A., et-al. (2002). Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109, 625–637.PubMedGoogle Scholar
  34. Hirota, S., Isozaki, K., Moriyama, Y., Hashimoto, K., Nishida, T., Ishiguro, S., Kawano, K., Hanada, M., Kurata, A., Takeda, M., et-al. (1998). Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279, 577–580.PubMedGoogle Scholar
  35. Hock, H., Hamblen, M. J., Rooke, H. M., Schindler, J. W., Saleque, S., Fujiwara, Y., and Orkin, S. H. (2004). Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature 431, 1002–1007.PubMedGoogle Scholar
  36. Ichikawa, M., Asai, T., Saito, T., Seo, S., Yamazaki, I., Yamagata, T., Mitani, K., Chiba, S., Ogawa, S., Kurokawa, M., and Hirai, H. (2004). AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nat Med 10, 299–304.PubMedGoogle Scholar
  37. Iwama, A., Oguro, H., Negishi, M., Kato, Y., Morita, Y., Tsukui, H., Ema, H., Kamijo, T., Katoh-Fukui, Y., Koseki, H., et-al. (2004). Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity 21, 843–851.PubMedGoogle Scholar
  38. Jacobson, L. O., Marks, E. K., and Lorenz, E. (1949). The hematological effects of ionizing radiations. Radiology 52, 371–395.PubMedGoogle Scholar
  39. Janzen, V., Forkert, R., Fleming, H. E., Saito, Y., Waring, M. T., Dombkowski, D. M., Cheng, T., DePinho, R. A., Sharpless, N. E., and Scadden, D. T. (2006). Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443, 421–426.PubMedGoogle Scholar
  40. Jude, C. D., Climer, L., Xu, D., Artinger, E., Fisher, J. K., and Ernst, P. (2007). Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. Cell Stem Cell 1, 324–337.PubMedGoogle Scholar
  41. Jude, C. D., Gaudet, J., Speck, N., and Ernst, P. (2008). Leukemia and hematopoietic stem cells: balancing proliferation and quiescence. Cell Cycle 7, 586–591.PubMedGoogle Scholar
  42. Kajiume, T., Ninomiya, Y., Ishihara, H., Kanno, R., and Kanno, M. (2004). Polycomb group gene mel-18 modulates the self-renewal activity and cell cycle status of hematopoietic stem cells. Exp Hematol 32, 571–578.PubMedGoogle Scholar
  43. Katayama, N., Shih, J. P., Nishikawa, S., Kina, T., Clark, S. C., and Ogawa, M. (1993). Stage-specific expression of c-kit protein by murine hematopoietic progenitors. Blood 82, 2353–2360.PubMedGoogle Scholar
  44. Kaushansky, K. (2006). Lineage-specific hematopoietic growth factors. N Engl J Med 354, 2034–2045.PubMedGoogle Scholar
  45. Kiel, M. J., Yilmaz, O. H., Iwashita, T., Yilmaz, O. H., Terhorst, C., and Morrison, S. J. (2005). SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothe-lial niches for stem cells. Cell 121, 1109–1121.PubMedGoogle Scholar
  46. Kile, B. T., and Hilton, D. J. (2005). The art and design of genetic screens: mouse. Nat Rev Genet 6, 557–567.PubMedGoogle Scholar
  47. Kim, I., He, S., Yilmaz, O. H., Kiel, M. J., and Morrison, S. J. (2006). Enhanced purification of fetal liver hematopoietic stem cells using SLAM family receptors. Blood 108, 737–744.PubMedGoogle Scholar
  48. Kim, M., Cooper, D. D., Hayes, S. F., and Spangrude, G. J. (1998). Rhodamine-123 staining in hematopoietic stem cells of young mice indicates mitochondrial activation rather than dye efflux. Blood 91, 4106–4117.PubMedGoogle Scholar
  49. Kirito, K., Fox, N., and Kaushansky, K. (2003). Thrombopoietin stimulates Hoxb4 expression: an explanation for the favorable effects of TPO on hematopoietic stem cells. Blood 102, 3172–3178.PubMedGoogle Scholar
  50. Kirito, K., Fox, N., and Kaushansky, K. (2004). Thrombopoietin induces HOXA9 nuclear transport in immature hematopoietic cells: potential mechanism by which the hormone favorably affects hematopoietic stem cells. Mol Cell Biol 24, 6751–6762.PubMedGoogle Scholar
  51. Kirstetter, P., Anderson, K., Porse, B. T., Jacobsen, S. E., and Nerlov, C. (2006). Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat Immunol 7, 1048–1056.PubMedGoogle Scholar
  52. Krosl, J., Austin, P., Beslu, N., Kroon, E., Humphries, R. K., and Sauvageau, G. (2003). In vitro expansion of hematopoietic stem cells by recombinant TAT-HOXB4 protein. Nat Med 9, 1428–1432.PubMedGoogle Scholar
  53. Ku, H., Yonemura, Y., Kaushansky, K., and Ogawa, M. (1996). Thrombopoietin, the ligand for the Mpl receptor, synergizes with steel factor and other early acting cytokines in supporting proliferation of primitive hematopoietic progenitors of mice. Blood 87, 4544–4551.PubMedGoogle Scholar
  54. Kyba, M., Perlingeiro, R. C., and Daley, G. Q. (2002). HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. Cell 109, 29–37.PubMedGoogle Scholar
  55. Lacorazza, H. D., Yamada, T., Liu, Y., Miyata, Y., Sivina, M., Nunes, J., and Nimer, S. D. (2006). The transcription factor MEF/ELF4 regulates the quiescence of primitive hematopoietic cells. Cancer Cell 9, 175–187.PubMedGoogle Scholar
  56. Lambert, J. F., Liu, M., Colvin, G. A., Dooner, M., McAuliffe, C. I., Becker, P. S., Forget, B. G., Weissman, S. M., and Quesenberry, P. J. (2003). Marrow stem cells shift gene expression and engraftment phenotype with cell cycle transit. J Exp Med 197, 1563–1572.PubMedGoogle Scholar
  57. Legrand, N., Weijer, K., and Spits, H. (2008). Experimental model for the study of the human immune system: production and monitoring of “human immune system” Rag2 —/— g c —/— mice. Methods Mol Biol 415, 65–82.PubMedGoogle Scholar
  58. Lessard, J., and Sauvageau, G. (2003). Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260. Liang, Y., Jansen, M., Aronow, B., Geiger, H., and Van Zant, G. (2007). The quantitative trait gene latexin influences the size of the hematopoietic stem cell population in mice. Nat Genet 39, 178–188.PubMedGoogle Scholar
  59. Lyman, S. D., and Jacobsen, S. E. (1998). c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 91, 1101–1134.PubMedGoogle Scholar
  60. Malynn, B. A., de Alboran, I. M., O'Hagan, R. C., Bronson, R., Davidson, L., DePinho, R. A., and Alt, F. W. (2000). N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation. Genes Dev 14, 1390–1399.PubMedGoogle Scholar
  61. Mazurier, F., Doedens, M., Gan, O. I., and Dick, J. E. (2003). Rapid myeloerythroid repopulation after intrafemoral transplantation of NOD-SCID mice reveals a new class of human stem cells. Nat Med 9, 959–963.PubMedGoogle Scholar
  62. McCulloch, E. A., Siminovitch, L., Till, J. E., Russell, E. S., and Bernstein, S. E. (1965). The cellular basis of the genetically determined hemopoietic defect in anemic mice of genotype Sl-Sld. Blood 26, 399–410.PubMedGoogle Scholar
  63. McKenzie, J. L., Takenaka, K., Gan, O. I., Doedens, M., and Dick, J. E. (2007). Low rhodamine 123 retention identifies long-term human hematopoietic stem cells within the Lin — CD34 + CD38 — population. Blood 109, 543–545.PubMedGoogle Scholar
  64. McMahon, A. P., Ingham, P. W., and Tabin, C. J. (2003). Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol 53, 1–114.PubMedGoogle Scholar
  65. McMahon, K. A., Hiew, S. Y., Hadjur, S., Veiga-Fernandes, H., Menzel, U., Price, A. J., Kioussis, D., Williams, O., and Brady, H. J. (2007). Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal. Cell Stem Cell 1, 338–345.PubMedGoogle Scholar
  66. Meyers, S., and Hiebert, S. W. (1995). Indirect and direct disruption of transcriptional regulation in cancer: E2F and AML-1. Crit Rev Eukaryot Gene Expr 5, 365–383.PubMedGoogle Scholar
  67. Miller, C. L., Rebel, V. I., Helgason, C. D., Lansdorp, P. M., and Eaves, C. J. (1997). Impaired steel factor responsiveness differentially affects the detection and long-term maintenance of fetal liver hematopoietic stem cells in vivo. Blood 89, 1214–1223.PubMedGoogle Scholar
  68. Miyamoto, K., Araki, K. Y., Naka, K., Arai, F., Takubo, K., Yamazaki, S., Matsuoka, S., Miyamoto, T., Ito, K., Ohmura, M., et-al. (2007). Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1, 101–112.PubMedGoogle Scholar
  69. Morrison, S. J., and Weissman, I. L. (1994). The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1, 661–673.PubMedGoogle Scholar
  70. Nolta, J. A., Hanley, M. B., and Kohn, D. B. (1994). Sustained human hematopoiesis in immuno-deficient mice by cotransplantation of marrow stroma expressing human interleukin-3: analysis of gene transduction of long-lived progenitors. Blood 83, 3041–3051.PubMedGoogle Scholar
  71. Ogawa, M., Matsuzaki, Y., Nishikawa, S., Hayashi, S., Kunisada, T., Sudo, T., Kina, T., Nakauchi, H., and Nishikawa, S. (1991). Expression and function of c-kit in hemopoietic progenitor cells. J Exp Med 174, 63–71.PubMedGoogle Scholar
  72. Ogawa, M., Nishikawa, S., Yoshinaga, K., Hayashi, S., Kunisada, T., Nakao, J., Kina, T., Sudo, T., Kodama, H., and Nishikawa, S. (1993). Expression and function of c-Kit in fetal hemopoietic progenitor cells: transition from the early c-Kit-independent to the late c-Kit-dependent wave of hemopoiesis in the murine embryo. Development 117, 1089–1098.PubMedGoogle Scholar
  73. Ohta, H., Sawada, A., Kim, J. Y., Tokimasa, S., Nishiguchi, S., Humphries, R. K., Hara, J., and Takihara, Y. (2002). Polycomb group gene rae28 is required for sustaining activity of hematopoi-etic stem cells. J Exp Med 195, 759–770.PubMedGoogle Scholar
  74. Opferman, J. T. (2007). Life and death during hematopoietic differentiation. Curr Opin Immunol 19, 497–502.PubMedGoogle Scholar
  75. Opferman, J. T., Iwasaki, H., Ong, C. C., Suh, H., Mizuno, S., Akashi, K., and Korsmeyer, S. J. (2005). Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307, 1101–1104.PubMedGoogle Scholar
  76. Park, I. K., Qian, D., Kiel, M., Becker, M. W., Pihalja, M., Weissman, I. L., Morrison, S. J., and Clarke, M. F. (2003). Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305.PubMedGoogle Scholar
  77. Passegue, E., Wagner, E. F., and Weissman, I. L. (2004). JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 119, 431–443.PubMedGoogle Scholar
  78. Passegue, E., Wagers, A. J., Giuriato, S., Anderson, W. C., and Weissman, I. L. (2005). Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med 202, 1599–1611.PubMedGoogle Scholar
  79. Petit-Cocault, L., Volle-Challier, C., Fleury, M., Peault, B., and Souyri, M. (2007). Dual role of Mpl receptor during the establishment of definitive hematopoiesis. Development 134, 3031–3040.PubMedGoogle Scholar
  80. Puri, M. C., and Bernstein, A. (2003). Requirement for the TIE family of receptor tyrosine kinases in adult but not fetal hematopoiesis. Proc Natl Acad Sci USA 100, 12753–12758.PubMedGoogle Scholar
  81. Renneville, A., Roumier, C., Biggio, V., Nibourel, O., Boissel, N., Fenaux, P., and Preudhomme, C. (2008). Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia 22, 915–931.PubMedGoogle Scholar
  82. Reya, T., Duncan, A. W., Ailles, L., Domen, J., Scherer, D. C., Willert, K., Hintz, L., Nusse, R., and Weissman, I. L. (2003). A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423, 409–414.PubMedGoogle Scholar
  83. Rodewald, H. R., and Sato, T. N. (1996). Tie1, a receptor tyrosine kinase essential for vascular endothelial cell integrity, is not critical for the development of hematopoietic cells. Oncogene 12, 397–404.PubMedGoogle Scholar
  84. Saito, R. M., Perreault, A., Peach, B., Satterlee, J. S., and van den Heuvel, S. (2004). The CDC-14 phosphatase controls developmental cell-cycle arrest in C. elegans. Nat Cell Biol 6, 777–783.Google Scholar
  85. Sandberg, M. L., Sutton, S. E., Pletcher, M. T., Wiltshire, T., Tarantino, L. M., Hogenesch, J. B., and Cooke, M. P. (2005). c-Myb and p300 regulate hematopoietic stem cell proliferation and differentiation. Dev Cell 8, 153–166.PubMedGoogle Scholar
  86. Sauvageau, G., Thorsteinsdottir, U., Eaves, C. J., Lawrence, H. J., Largman, C., Lansdorp, P. M., and Humphries, R. K. (1995). Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev 9, 1753–1765.PubMedGoogle Scholar
  87. Scheller, M., Huelsken, J., Rosenbauer, F., Taketo, M. M., Birchmeier, W., Tenen, D. G., and Leutz, A. (2006). Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation. Nat Immunol 7, 1037–1047.PubMedGoogle Scholar
  88. Schmidt, T., Zornig, M., Beneke, R., and Moroy, T. (1996). MoMuLV proviral integrations identified by Sup-F selection in tumors from infected myc/pim bitransgenic mice correlate with activation of the gfi-1 gene. Nucleic Acids Res 24, 2528–2534.PubMedGoogle Scholar
  89. Schroeder, T. (2005). Tracking hematopoiesis at the single cell level. Ann NY Acad Sci 1044, 201–209.PubMedGoogle Scholar
  90. Sitnicka, E., Lin, N., Priestley, G. V., Fox, N., Broudy, V. C., Wolf, N. S., and Kaushansky, K. (1996). The effect of thrombopoietin on the proliferation and differentiation of murine hemat-opoietic stem cells. Blood 87, 4998–5005.PubMedGoogle Scholar
  91. Snoeck, H. W. (2005). Quantitative trait analysis in the investigation of function and aging of hematopoietic stem cells. Methods Mol Med 105, 47–62.PubMedGoogle Scholar
  92. Souyri, M., Vigon, I., Penciolelli, J. F., Heard, J. M., Tambourin, P., and Wendling, F. (1990). A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors. Cell 63, 1137–1147.PubMedGoogle Scholar
  93. Spangrude, G. J., and Scollay, R. (1990). A simplified method for enrichment of mouse hemat-opoietic stem cells. Exp Hematol 18, 920–926.PubMedGoogle Scholar
  94. Sparmann, A., and van Lohuizen, M. (2006). Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 6, 846–856.PubMedGoogle Scholar
  95. Szilvassy, S. J., Humphries, R. K., Lansdorp, P. M., Eaves, A. C., and Eaves, C. J. (1990). Quantitative assay for totipotent reconstituting hematopoietic stem cells by a competitive repopulation strategy. Proc Natl Acad Sci USA 87, 8736–8740.PubMedGoogle Scholar
  96. Tajima, Y., Moore, M. A., Soares, V., Ono, M., Kissel, H., and Besmer, P. (1998). Consequences of exclusive expression in vivo of Kit-ligand lacking the major proteolytic cleavage site. Proc Natl Acad Sci USA 95, 11903–11908.PubMedGoogle Scholar
  97. Till, J. E., and McCulloch, C. E. (1961). A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14, 213–222.PubMedGoogle Scholar
  98. Tothova, Z., Kollipara, R., Huntly, B. J., Lee, B. H., Castrillon, D. H., Cullen, D. E., McDowell, E. P., Lazo-Kallanian, S., Williams, I. R., Sears, C., et-al. (2007). FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339.PubMedGoogle Scholar
  99. Trowbridge, J. J., Scott, M. P., and Bhatia, M. (2006). Hedgehog modulates cell cycle regulators in stem cells to control hematopoietic regeneration. Proc Natl Acad Sci USA 103, 14134–14139.PubMedGoogle Scholar
  100. Uchida, N., Dykstra, B., Lyons, K. J., Leung, F. Y., and Eaves, C. J. (2003). Different in vivo repopulating activities of purified hematopoietic stem cells before and after being stimulated to divide in vitro with the same kinetics. Exp Hematol 31, 1338–1347.PubMedGoogle Scholar
  101. Umemoto, T., Yamato, M., Nishida, K., Yang, J., Tano, Y., and Okano, T. (2005). p57Kip2 is expressed in quiescent mouse bone marrow side population cells. Biochem Biophys Res Commun 337, 14–21.PubMedGoogle Scholar
  102. Urso, P., and Congdon, C. C. (1957). The effect of the amount of isologous bone marrow injected on the recovery of hematopoietic organs, survival and body weight after lethal irradiation injury in mice. Blood 12, 251–260.PubMedGoogle Scholar
  103. van der Lugt, N. M., Alkema, M., Berns, A., and Deschamps, J. (1996). The Polycomb-group homolog Bmi-1 is a regulator of murine Hox gene expression. Mech Dev 58, 153–164.PubMedGoogle Scholar
  104. Willert, K., Brown, J. D., Danenberg, E., Duncan, A. W., Weissman, I. L., Reya, T., Yates, J. R., III, and Nusse, R. (2003). Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448–452.PubMedGoogle Scholar
  105. Wilson, A., Murphy, M. J., Oskarsson, T., Kaloulis, K., Bettess, M. D., Oser, G. M., Pasche, A. C., Knabenhans, C., Macdonald, H. R., and Trumpp, A. (2004). c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev 18, 2747–2763.PubMedGoogle Scholar
  106. Wissler, R. W., Robson, M. J., Fitch, F., Nelson, W., and Jacobson, L. O. (1953). The effects of spleen shielding and subsequent splenectomy upon antibody formation in rats receiving total-body X-irradiation. J Immunol 70, 379–385.PubMedGoogle Scholar
  107. Wu, M., Kwon, H. Y., Rattis, F., Blum, J., Zhao, C., Ashkenazi, R., Jackson, T. L., Gaiano, N., Oliver, T., and Reya, T. (2007). Imaging hematopoietic precursor division in real time. Cell Stem Cell 1, 541–554.PubMedGoogle Scholar
  108. Yang, L., Wang, L., Geiger, H., Cancelas, J. A., Mo, J., and Zheng, Y. (2007). Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow. Proc Natl Acad Sci USA 104, 5091–5096.PubMedGoogle Scholar
  109. Yilmaz, O. H., Kiel, M. J., and Morrison, S. J. (2006a). SLAM family markers are conserved among hematopoietic stem cells from old and reconstituted mice and markedly increase their purity. Blood 107, 924–930.Google Scholar
  110. Yilmaz, O. H., Valdez, R., Theisen, B. K., Guo, W., Ferguson, D. O., Wu, H., and Morrison, S. J. (2006b). Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482.Google Scholar
  111. Yokota, S., Kiyoi, H., Nakao, M., Iwai, T., Misawa, S., Okuda, T., Sonoda, Y., Abe, T., Kahsima, K., Matsuo, Y., and Naoe, T. (1997). Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. Leukemia 11, 1605–1609.Google Scholar
  112. Yoshihara, H., Arai, F., Hosokawa, K., Hagiwara, T., Keiyo, T., Nakamura, Y., Gomei, Y., Iwasaki, H., Matsuoka, S., Miyamoto, K., et-al. (2007). Thrombin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell 1, 685–697.PubMedGoogle Scholar
  113. Yu, H., Yuan, Y., Shen, H., and Cheng, T. (2006). Hematopoietic stem cell exhaustion impacted by p18 INK4C and p21 Cip1/Waf1 in opposite manners. Blood 107, 1200–1206.PubMedGoogle Scholar
  114. Yuan, Y., Shen, H., Franklin, D. S., Scadden, D. T., and Cheng, T. (2004). In vivo self-renewing divisions of haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18INK4C. Nat Cell Biol 6, 436–442.PubMedGoogle Scholar
  115. Zanjani, E. D., Almeida-Porada, G., and Flake, A. W. (1996). The human/sheep xenograft model: a large animal model of human hematopoiesis. Int J Hematol 63, 179–192.PubMedGoogle Scholar
  116. Zeng, H., Yucel, R., Kosan, C., Klein-Hitpass, L., and Moroy, T. (2004). Transcription factor Gfi1 regulates self-renewal and engraftment of hematopoietic stem cells. EMBO J 23, 4116–4125.PubMedGoogle Scholar
  117. Zhang, J., Grindley, J. C., Yin, T., Jayasinghe, S., He, X. C., Ross, J. T., Haug, J. S., Rupp, D., Porter-Westpfahl, K. S., Wiedemann, L. M., et-al. (2006). PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 441, 518–522.PubMedGoogle Scholar
  118. Zhang, P., Liegeois, N. J., Wong, C., Finegold, M., Hou, H., Thompson, J. C., Silverman, A., Harper, J. W., DePinho, R. A., and Elledge, S. J. (1997). Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature 387, 151–158.PubMedGoogle Scholar
  119. Zhou, S., Schuetz, J. D., Bunting, K. D., Colapietro, A. M., Sampath, J., Morris, J. J., Lagutina, I., Grosveld, G. C., Osawa, M., Nakauchi, H., and Sorrentino, B. P. (2001). The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7, 1028–1034.PubMedGoogle Scholar
  120. Zijlmans, J. M., Visser, J. W., Kleiverda, K., Kluin, P. M., Willemze, R., and Fibbe, W. E. (1995). Modification of rhodamine staining allows identification of hematopoietic stem cells with preferential short-term or long-term bone marrow-repopulating ability. Proc Natl Acad Sci USA 92, 8901–8905.PubMedGoogle Scholar
  121. Zindy, F., Quelle, D. E., Roussel, M. F., and Sherr, C. J. (1997). Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 15, 203–211.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Genetics Norris Cotton Cancer CenterDartmouth Medical School 725 RemsenUSA

Personalised recommendations