Developmental Origins of Hematopoietic Stem Cells

  • Elaine Dzierzak
  • Alexander Medvinsky
Part of the Contemporary Immunology book series (CONTIM)


The hemato/lymphopoietic system is a dynamic continuum of differentiating cells leading to the production of numerous lineages of blood effector cells. In the adult, only a few immature undifferentiated hematopoietic stem cells are required to yield the enormous number of intermediate progenitors and effector cells produced daily. Although these founder cells of the adult mammalian blood system have been extensively studied, the developmental origins of definitive hematopoietic stem cells are controversial, and the subject of much current research. In this article, the authors review studies that explore the ontogeny of the hemato/lymphopoietic system and present current models of initiation, migration, lineage potential, and molecular programming of the cells involved in establishing the complex network in the adult. The combined results of studies on the origin and function suggest distinct embryonic and adult hierarchies on the cellular levels, whereas molecular studies suggest some, but not complete, overlap in the genetic programming of embryonic and adult hematopoietic cells.


Hematopoietic Stem Cell Hematopoietic Cell Fetal Liver Hematopoietic Progenitor Adult Bone Marrow 
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.


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  1. 1.
    Morrison, S. J., Uchida, N., and Weissman, I. L. (1995) The biology ofhematopoietic stem cells. Ann. Rev. Cell. Dey. Biol. 11, 35–71.CrossRefGoogle Scholar
  2. 2.
    Abramson, S., Miller, R. G., and Phillips, R. A. (1977) The identification in adult bone marrow of pluripotent and restricted stem cells of the myeloid and lymphoid systems. J. Exp. Med. 145, 1567–1579.PubMedCrossRefGoogle Scholar
  3. 3.
    Micklem, H. S., Ford, C. E., Evans, E. P., and Gray, J. (1966) Interrelationships of myeloid and lymphoid cells: studies with chromosome-marked cells transfused into lethally irradiated mice. Proc. R. Soc. Lond. B. Biol. Sci. 165, 78–102.PubMedCrossRefGoogle Scholar
  4. 4.
    Capel, B., Hawley, R., Covarrubias, L., Hawley, T., and Mintz, B. (1989) Clonal contributions of small numbers of retrovirally marked hematopoietic stem cells engrafted in unirradiated neonatal W/Wv mice [published erratum appears in Proc Natl Acad Sci U S A 1989 Sep;86(18):7048]. Proc. Natl. Acad. Sci. USA 86, 4564–4568.PubMedCrossRefGoogle Scholar
  5. 5.
    Dick, J. E., Magli, M. C., Huszar, D., Phillips, R. A., and Bernstein, A. (1985) Introduction of a selectable gene into primitive stem cells capable of long-term reconstitution of the hemopoietic system of W/Wv mice. Cell 42, 71–79.Google Scholar
  6. 6.
    Jordan, C. T., McKearn, J. P., and Lemischka, I. R. (1990) Cellular and developmental properties of fetal hematopoietic stem cells. Cell 61, 953–963.Google Scholar
  7. 7.
    Keller, G., Paige, C., Gilboa, E., and Wagner, E. F. (1985) Expression of a foreign gene in myeloid and lymphoid cells derived from multipotent haematopoietic precursors. Nature 318, 149–154.PubMedCrossRefGoogle Scholar
  8. 8.
    Lemischka, I. R., Raulet, D. H., and Mulligan, R. C. (1986) Developmental potential and dynamic behavior of hematopoietic stem cells. Cell 45, 917–927.PubMedCrossRefGoogle Scholar
  9. 9.
    Till, J. and E. McCulloch. (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiation Res. 14, 213–222.PubMedCrossRefGoogle Scholar
  10. 10.
    Magli, M. C., Iscove, N. N., and Odartchenko, N. (1982) Transient nature of early haematopoietic spleen colonies. Nature 295, 527–529.PubMedCrossRefGoogle Scholar
  11. 11.
    Jones, R. J., Wagner, J. E., Celano, P., Zicha, M. S., and Sharkis, S. J. (1990) Separation of pluripotent haematopoietic stem cells from spleen colony-forming cells [see comments]. Nature 347, 188–189.PubMedCrossRefGoogle Scholar
  12. 12.
    Metcalf, D. (1984) The hemopoietic colony stimulating factors. Elsevier Science Publishers B. V., Amsterdam.Google Scholar
  13. 13.
    Whitlock, C. A. and Witte, O. N. (1982) Long-term culture of B lymphocytes and their precursors from murine bone marrow. Proc. Natl. Acad. Sci. USA 79, 3608–3612.PubMedCrossRefGoogle Scholar
  14. 14.
    Jenkinson, E. J., Franchi, L. L., Kingston, R., and Owen, J. J. (1982) Effect of deoxyguanosine on lymphopoiesis in the developing thymus rudiment in vitro: application in the production of chimeric thymus rudiments. Eur. J. Immunol. 12, 583–587.PubMedCrossRefGoogle Scholar
  15. 15.
    Kawamoto, H. Ohmura, K., and Katsura, Y. (1997) Direct evidence for the commitment of hematopoietic stem cells to T, B and myeloid lineages in murine fetal liver. Int. Immunol. 9 1011–1019.Google Scholar
  16. 16.
    Snodgrass, R. and Keller, G. (1987) Clonal fluctuation within the haematopoietic system of mice reconstituted with retrovirus-infected stem cells. Embo. J. 6, 3955–3960.PubMedGoogle Scholar
  17. 17.
    Moore, M. A. and Metcalf, D. (1970) Ontogeny of the haemopoietic system: yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. Br. J. Haematol. 18, 279–296.PubMedCrossRefGoogle Scholar
  18. 18.
    Johnson, G. R. and Jones, R. O. (1973) Differentiation of the mammalian hepatic primordium in vitro. I. Morphogenesis and the onset of haematopoiesis. J. Embryol. Exp. Morphol. 30, 83–96.PubMedGoogle Scholar
  19. 19.
    Godin, I. E., Garcia-Porrero, J. A., Coutinho, A., Dieterlen-Lievre, F., and Marcos, M. A. (1993) Para-aortic splanchnopleura from early mouse embryos contains B la cell progenitors. Nature 364, 67–70.PubMedCrossRefGoogle Scholar
  20. 20.
    Medvinsky, A. L., Samoylina, N. L., Muller, A. M., and Dzierzak, E. A. (1993) An early pre-liver intraembryonic source of CFU-S in the developing mouse. Nature 364, 64–67.PubMedCrossRefGoogle Scholar
  21. 21.
    Muller, A. M., Medvinsky, A., Strouboulis, J., Grosveld, F., and Dzierzak, E. (1994) Development of hematopoietic stem cell activity in the mouse embryo. Immunity 1, 291–301.PubMedCrossRefGoogle Scholar
  22. 22.
    Russell, E. S. and Bernstein, S. E. (1966) Blood and blood formation, p. 351–372. in Biology of the Laboratory Mouse, 2nd ed. ( Green, E. L., ed.), McGraw-Hill, New York.Google Scholar
  23. 23.
    His, W. (1990) Lecithoblast and Angioblast der Wirbeltiere. Abhandl. Math-Phys. Ges. Wiss. 26, 171–328.Google Scholar
  24. 24.
    Cumano, A., Furlonger, C., and Paige, C. J. (1993) Differentiation and characterization of B-cell precursors detected in the yolk sac and embryo body of embryos beginning at the 10- to 12somite stage. Proc. Natl. Acad. Sci. USA 90, 6429–6433.PubMedCrossRefGoogle Scholar
  25. 25.
    Godin, I., Dieterlen-Lievre, F., and Cumano, A. (1995) B-lymphoid potential in pre-liver mouse embryo. Semin. Immunol. 7, 131–141.PubMedCrossRefGoogle Scholar
  26. 26.
    Huang, H. Zettergren, L. D., and Auerbach, R. (1994) In vitro differentiation of B cells and myeloid cells from the early mouse embryo and its extraembryonic yolk sac [see comments]. Exp. Hematol. 22 19–25.Google Scholar
  27. 27.
    Liu, C. P. and Auerbach, R. (1991) In vitro development of murine T cells from prethymic and preliver embryonic yolk sac hematopoietic stem cells. Development 113, 1315–1323.PubMedGoogle Scholar
  28. 28.
    Liu, C. P. and Auerbach, R. (1991) Ontogeny of murine T cells: thymus-regulated development of T cell receptor-bearing cells derived from embryonic yolk sac. Eur. J Immunol. 21, 1849–1855.PubMedCrossRefGoogle Scholar
  29. 29.
    Ogawa, M., Nishikawa, S., Ikuta, K., Yamamura, F., Naito, M., Takahashi, K., and Nishikawa, S. (1988) B cell ontogeny in murine embryo studied by a culture system with the monolayer of a stromal cell clone, ST2: B cell progenitor develops first in the embryonal body rather than in the yolk sac. Embo. J. 7, 1337–1343.PubMedGoogle Scholar
  30. 30.
    Medvinsky, A. L. (1993) Ontogeny of the mouse hematopoietic system. Sem. Dev. Biol. 4, 333–340.CrossRefGoogle Scholar
  31. 31.
    Medvinsky, A. and Dzierzak, E. (1996) Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86, 897–906.PubMedCrossRefGoogle Scholar
  32. 32.
    Cumano, A., Dieterlen-Lievre, F., and Godin, I. (1996) Lymphoid potential, probed before circulation in mouse, is restricted to caudal intraembryonic splanchnopleura. Cell 86, 907–916.PubMedCrossRefGoogle Scholar
  33. 33.
    Johnson, G. R. and Moore, M. A. (1975) Role of stem cell migration in initiation of mouse foetal liver haemopoiesis. Nature 258, 726–728.PubMedCrossRefGoogle Scholar
  34. 34.
    Houssaint, E. (1981) Differentiation of the mouse hepatic primordium. II. Extrinsic origin of the haemopoietic cell line. Cell Differ. 10, 243–252.PubMedCrossRefGoogle Scholar
  35. 35.
    Eren, R., Zharhary, D., Abel, L., and Globerson, A. (1987) Ontogeny of T cells: development ofpreT cells from fetal liver and yolk sac in the thymus microenvironment. Cell Immunol. 108, 76–84.PubMedCrossRefGoogle Scholar
  36. 36.
    Morris, L., Crocker, P. R., Fraser, I., Hill, M., and Gordon, S. (1991) Expression of a divalent cation-dependent erythroblast adhesion receptor by stromal macrophages from murine bone marrow. J. Cell. Sci. 99, 141–147.Google Scholar
  37. 37.
    Velardi, A. and Cooper, M. D. (1984) An immunofluorescence analysis of the ontogeny of myeloid, T, and B lineage cells in mouse hemopoietic tissues. J. Immunol. 133, 672–677.PubMedGoogle Scholar
  38. 38.
    Medvinsky, A. L., Gan, O. I., Semenova, M. L., and Samoylina, N. L. (1996) Development of day-8 colony-forming unit-spleen hematopoietic progenitors during early murine embryogenesis: spatial and temporal mapping. Blood 87, 557–566.PubMedGoogle Scholar
  39. 39.
    Dzierzak, E. and Medvinsky, A. (1995) Mouse embryonic hematopoiesis. Trends Genet. 11, 359–366.PubMedCrossRefGoogle Scholar
  40. 40.
    Dieterlen-Lievre, F. and Le Douarin, N. M. (1993) Developmental rules in the hematopoietic and immune systems of birds: how general are they? Sem. Dev. Biol. 4, 325–332.CrossRefGoogle Scholar
  41. 41.
    Zon, L. I. (1995) Developmental biology of hematopoiesis. Blood 86, 2876–2891.PubMedGoogle Scholar
  42. 42.
    Dieterlen-Lievre, F. (1975) On the origin of haemopoietic stem cells in the avian embryo: an experimental approach. J. Embryol. Exp. Morphol. 33, 607–619.PubMedGoogle Scholar
  43. 43.
    Turpen, J. B., Knudson, C. M., and Hoefen, P. S. (1981) The early ontogeny of hematopoietic cells studied by grafting cytogenetically labeled tissue anlagen: localization of a prospective stem cell compartment. Dev. Biol. 85, 99–112.PubMedCrossRefGoogle Scholar
  44. 44.
    Dieterlen-Lievre, F. and Martin, C. (1981) Diffuse intraembryonic hemopoiesis in normal and chimeric avian development. Dev. Biol. 88, 180–191.PubMedCrossRefGoogle Scholar
  45. 45.
    Cormier, F. and Dieterlen-Lievre, F. (1988) The wall of the chick embryo aorta harbours M-CFC, G-CFC, GM-CFC and BFU-E. Development 102, 279–285.PubMedGoogle Scholar
  46. 46.
    Turpen, J. B., Knudson, C. M., and Hoefen, P. S. (1981) The early ontogeny of hematopoietic cells studied by grafting cytogenetically labeled tissue anlagen: localization of a prospective stem cell compartment. Dev. Biol. 85, 99–112.PubMedCrossRefGoogle Scholar
  47. 47.
    Kau, C. L. and Turpen, J. B. (1983) Dual contribution of embryonic ventral blood island and dorsal lateral plate mesoderm during ontogeny of hemopoietic cells in Xenopus laevis. J Immunol 131, 2262–2266.PubMedGoogle Scholar
  48. 48.
    Maeno, M., Tochinai, S., and Katagiri, C. (1985) Differential participation of ventral and dorsolateral mesoderms in the hemopoiesis of Xenopus, as revealed in diploid-triploid or inter-specific chimeras. Dev. Biol. 110, 503–508.PubMedCrossRefGoogle Scholar
  49. 49.
    Bodine, D. (1995) Mobilization of peripheral blood `stem’ cells: where there is smoke, is there fire? [editorial; comment]. Exp. Hematol. 23, 293–295.PubMedGoogle Scholar
  50. 50.
    Cronkite, E. (1997) Response to “Mobilization of peripheral blood `stem’ cells: Where there is smoke, is there fire?” Yes, there have been many fires, leaving cold coals. Experimen. Hematol. 25, 185–186.Google Scholar
  51. 51.
    Delassus, S. and Cumano, A. (1996) Circulation of hematopoietic progenitors in the mouse embryo. Immunity 4, 97–106.PubMedCrossRefGoogle Scholar
  52. 52.
    Le Douarin, N. M., Dieterlen-Lievre, F., and Oliver, P. D. (1984) Ontogeny of primary lymphoid organs and lymphoid stem cells. Am. J. Anat. 170, 261–299.PubMedCrossRefGoogle Scholar
  53. 53.
    Coltey, M., Jotereau, F. V., and Le Douarin, N. M. (1987) Evidence for a cyclic renewal of lymphocyte precursor cells in the embryonic chick thymus. Cell Differ. 22, 71–82.PubMedCrossRefGoogle Scholar
  54. 54.
    Le Douarin, N. M., Houssaint, E., Jotereau, F. V., and Belo, M. (1975) Origin of hemopoietic stem cells in embryonic bursa of Fabricius and bone marrow studied through interspecific chimeras. Proc. Natl. Acad. Sci. USA 72, 2701–2705.PubMedCrossRefGoogle Scholar
  55. 55.
    Martin, C., Beaupain, D., and Dieterlen-Lievre, F. (1978) Developmental relationships between vitelline and intra-embryonic haemopoiesis studied in avian `yolk sac chimaeras’. Cell. Dyer. 7, 115–130.Google Scholar
  56. 56.
    Chen, X. D. and Turpen, J. B. (1995) Intraembryonic origin of hepatic hematopoiesis in Xeno-pus laevis. J. Immunol. 154, 2557–2567.PubMedGoogle Scholar
  57. 57.
    Bechtold, T. E., Smith, P. B., and Turpen, J. B. (1992) Differential stem cell contributions to thymocyte succession during development of Xenopus laevis. J. Immunol. 148, 2975–2982.PubMedGoogle Scholar
  58. 58.
    Detrich, H. W. R., Kieran, M. W., Chan, F. Y., Barone, L. M., Yee, K., Rundstadler, J. A., Pratt, S., Ransom, D., and Zon, L. I. (1995) Intraembryonic hematopoietic cell migration during vertebrate development. Proc. Natl. Acad. Sci. USA 92, 10,713–10, 717.Google Scholar
  59. 59.
    Neave, B., Rodaway, A., Wilson, S. W., Patient, R., and Holder, N. (1995) Expression of zebrafish GATA 3 (gta3) during gastrulation and neurulation suggests a role in the specification of cell fate. Mech. Dev. 51, 169–182.PubMedCrossRefGoogle Scholar
  60. 60.
    Cudennec, C. A., Thiery, J. P., and Le Douarin, N. M. (1981) In vitro induction of adult erythropoiesis in early mouse yolk sac. Proc. Natl. Acad. Sci. USA 78, 2412–2416.PubMedCrossRefGoogle Scholar
  61. 61.
    Spangrude, G. J., Heimfeld, S., and Weissman, I. L. (1988) Purification and characterization of mouse hematopoietic stem cells [published erratum appears in Science 1989 Jun 2;244(4908):1030]. Science 241, 58–62.PubMedCrossRefGoogle Scholar
  62. 62.
    Uchida, N. and Weissman, I. L. (1992) Searching for hematopoietic stem cells: evidence that Thy-1.110 Lin- Sca-1+ cells are the only stem cells in C57BL/Ka-Thy-1.1 bone marrow. J. Exp. Med. 175, 175–184.PubMedCrossRefGoogle Scholar
  63. 63.
    Sanchez, M. J., Holmes, A., Miles, C., and Dzierzak, E. (1996) Characterization of the first definitive hematopoietic stem cells in the AGM and liver of the mouse embryo. Immunity 5, 513–525.PubMedCrossRefGoogle Scholar
  64. 64.
    Morrison, S. J., Hemmati, H. D., Wandycz, A. M., and Weissman, I. L. (1995) The purification and characterization of fetal liver hematopoietic stem cells. Proc. Natl. Acad. Sci. USA 92, 10,302–10, 306.Google Scholar
  65. 65.
    Huang, H. and Auerbach, R. (1993) Identification and characterization of hematopoietic stem cells from the yolk sac of the early mouse embryo. Proc. Natl. Acad. Sci. USA 90, 10,110–10, 114.Google Scholar
  66. 66.
    Wijgerde, M., Grosveld, F., and Fraser, P. (1995) Transcription complex stability and chromatin dynamics in vivo. Nature 377, 209–213.Google Scholar
  67. 67.
    Ingram, V. M. (1972) Embryonic red blood cell formation. Nature 235, 338–339.PubMedCrossRefGoogle Scholar
  68. 68.
    Wong, P. M., Chung, S. W., Reicheld, S. M., and Chui, D. H. (1986) Hemoglobin switching during murine embryonic development: evidence for two populations of embryonic erythropoietic progenitor cells. Blood 67, 716–721.PubMedGoogle Scholar
  69. 69.
    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.Google Scholar
  70. 70.
    Ikuta, K., Kina, T., MacNeil, I., Uchida, N., Peault, B., Chien, Y. H., and Weissman, I. L. (1990) A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell 62, 863–874.PubMedCrossRefGoogle Scholar
  71. 71.
    Hayakawa, K., Hardy, R. R., Herzenberg, L. A., and Herzenberg, L. A. (1985) Progenitors for Ly-1 B cells are distinct from progenitors for other B cells. J. Exp. Med. 161, 1554–1568.PubMedCrossRefGoogle Scholar
  72. 72.
    Herzenberg, L. A., Stall, A. M., Lalor, P. A., Sidman, C., Moore, W. A., Parks, D. R., and Herzenberg, L. A. (1986) The Ly-1 B cell lineage. Immunol. Rev. 93, 81–102.PubMedCrossRefGoogle Scholar
  73. 73.
    Naito, M. (1993) Macrophage heterogeneity in development and differentiation. Arch. Histol. Cytol. 56, 331–351.PubMedCrossRefGoogle Scholar
  74. 74.
    Naito, M., Umeda, S., Yamamoto, T., Moriyama, H., Umezu, H., Hasegawa, G., Usuda, H., Shultz, L. D., and Takahashi, K. (1996) Development, differentiation, and phenotypic heterogeneity of murine tissue macrophages. J. Leukoc. Biol. 59, 133–138.Google Scholar
  75. 75.
    Bruijn, M. D. (1997) PhD. Thesis. Macrophage progenitor cells in mouse bone marrow. Erasmus University, Rotterdam.Google Scholar
  76. 76.
    Shalaby, F., Rossant, J., Yamaguchi, T. P., Gertsenstein, M., Wu, X. F., Breitman, M. L., and Schuh, A. C. (1995) Failure of blood-island formation and vasculogenesis in Flk-1eficient mice. Nature 376, 62–66.PubMedCrossRefGoogle Scholar
  77. 77.
    Dickson, M. C., Martin, J. S., Cousins, F. M., Kulkarni, A. B., Karlsson, S., and Akhurst, R. J. (1995) Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development 121, 1845–1854.Google Scholar
  78. 78.
    Fong, G. H., Rossant, J., Gertsenstein, M., and Breitman, M. L. (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66–70.PubMedCrossRefGoogle Scholar
  79. 79.
    Puri, M. C., Rossant, J., Alitalo, K., Bernstein, A., and Partanen, J. (1995) The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. Embo. J. 14, 5884–5891.PubMedGoogle Scholar
  80. 80.
    Sato, T. N., Tozawa, Y., Deutsch, U., Wolburg-Buchholz, K., Fujiwara, Y., Gendron-Maguire, M., Gridley, T., Wolburg, H., Risau, W., and Qin, Y. (1995) Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376, 70–74.PubMedCrossRefGoogle Scholar
  81. 81.
    Porcher, C., Swat, W., Rockwell, K., Fujiwara, Y., Alt, F. W., and Orkin, S. H. (1996) The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. Cell 86, 47–57.PubMedCrossRefGoogle Scholar
  82. 82.
    Robb, L., Elwood, N. J., Elefanty, A. G., Kontgen, F., Li, R., Barnett, L. D., and Begley, C. G. (1996) The scl gene product is required for the generation of all hematopoietic lineages in the adult mouse. Embo. J. 15, 4123–4129.Google Scholar
  83. 83.
    Robb, L., Lyons, I., Li, R., Hartley, L., Kontgen, F., Harvey, R. P., Metcalf, D., and Begley, C. G. (1995) Absence of yolk sac hematopoiesis from mice with a targeted disruption of the scl gene. Proc. Natl. Acad. Sci. USA 92, 7075–7079.PubMedCrossRefGoogle Scholar
  84. 84.
    Shivdasani, R. A., Mayer, E. L., and Orkin, S. H. (1995) Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature 373, 432–434.PubMedCrossRefGoogle Scholar
  85. 85.
    Berger, C. N. and Sturm, K. S. (1996) Estimation of the number of hematopoietic precursor cells during fetal mouse development by covariance analysis. Blood 88, 2502–2509.PubMedGoogle Scholar
  86. 86.
    Tsai, F. Y., Keller, G., Kuo, F. C., Weiss, M., Chen, J., Rosenblatt, M., Alt, F. W., and Orkin, S. H. (1994) An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature 371, 221–226.PubMedCrossRefGoogle Scholar
  87. 87.
    Okuda, T., van Deursen, J., Hiebert, S. W., Grosveld, G., and Downing, J. R. (1996) AML 1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84, 321–330.PubMedCrossRefGoogle Scholar
  88. 88.
    Sasaki, K., Yagi, H., Bronson, R. T., Tominaga, K., Matsunashi, T., Deguchi, K., Tani, Y., Kishimoto, T., and Komori, T. (1996) Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor beta. Proc. Natl. Acad. Sci. USA 93, 12,359–12, 363.Google Scholar
  89. 89.
    Wang, Q., Stacy, T., Binder, M., Marin-Padilla, M., Sharpe, A. H., and Speck, N. A. (1996) Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc. Natl. Acad. Sci. USA 93, 3444–3449.PubMedCrossRefGoogle Scholar
  90. 90.
    Wang, Q., Stacy, T., Miller, J. D., Lewis, A. F., Gu, T. L., Huang, X., Bushweller, J. H., Bories, J. C., Alt, F. W., Ryan, G., Liu, P. P., Wynshaw-Boris, A., Binder, M., Marin-Padilla, M., Sharpe, A. H., and Speck, N. A. (1996) The CBFbeta subunit is essential for CBFalpha2 (AML 1) function in vivo. Cell 87, 697–708.PubMedCrossRefGoogle Scholar
  91. 91.
    Pandolfi, P. P., Roth, M. E., Karis, A., Leonard, M. W., Dzierzak, E., Grosveld, F. G., Engel, J. D., and Lindenbaum, M. H. (1995) Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis. Nat. Genet. 11, 40–44.PubMedCrossRefGoogle Scholar
  92. 92.
    Ting, C. N., Olson, M. C., Barton, K. P., and Leiden, J. M. (1996) Transcription factor GATA3 is required for development of the T-cell lineage. Nature 384, 474–478.Google Scholar
  93. 93.
    Lin, H. H., Sternfeld, D. C., Shinpock, S. G., Popp, R. A., and Mucenski, M. L. (1996) Functional analysis of the c-myb proto-oncogene. Curr. Top. Microbiol. Immunol. 211, 79–87.PubMedCrossRefGoogle Scholar
  94. 94.
    Mucenski, M. L., McLain, K., Kier, A. B., Swerdlow, S. H., Schreiner, C. M., Miller, T. A., Pietryga, D. W., Scott, W. J., Jr., and Potter, S. S. (1991) A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis. Cell 65, 677–689.PubMedCrossRefGoogle Scholar
  95. 95.
    McKercher, S. R., Torbett, B. E., Anderson, K. L., Henkel, G. W., Vestal, D. J., Baribault, H., Klemsz, M., Feeney, A. J., Wu, G. E., Paige, C. J., and Maki, R. A. (1996) Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. Embo. J. 15, 5647–5658.PubMedGoogle Scholar
  96. 96.
    Scott, E., Fisher, R., Olson, M., Kehrli, E., Simon, M., and Singh, H. (1997) PU.1 functions in a cell-autonomous manner to control the differentiation of multipotential lymphoid-myeloid progenitors. Immunity 6, 437–448.PubMedCrossRefGoogle Scholar
  97. 97.
    Scott, E. W., Simon, M. C., Anastasi, J., and Singh, H. (1994) Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science 265, 1573–1577.PubMedCrossRefGoogle Scholar
  98. 98.
    Okada, S., Nakauchi, H., Nagayoshi, K., Nishikawa, S., Nishikawa, S., Miura, Y., and Suda, T. (1991) Enrichment and characterization of murine hematopoietic stem cells that express c-kit molecule. Blood 78, 1706–1712.Google Scholar
  99. 99.
    Russell, E. S. (1979) Hereditary anemias of the mouse: a review for geneticists. Adv. Genet. 20, 357–459.PubMedCrossRefGoogle Scholar
  100. 100.
    Bernad, A., Kopf, M., Kulbacki, R., Weich, N., Koehler, G., and J. C. Gutierrez-Ramos. (1994) Interleukin-6 is required in vivo for the regulation of stem cells and committed progenitors of the hematopoietic system. Immunity 1, 725–731.PubMedCrossRefGoogle Scholar
  101. 101.
    Escary, J. L., Perreau, J., Dumenil, D., Ezine, S., and Brulet, P. (1993) Leukaemia inhibitory factor is necessary for maintenance of haematopoietic stem cells and thymocyte stimulation. Nature 363, 361–364.PubMedCrossRefGoogle Scholar
  102. 102.
    Mackarehtschian, K., Hardin, J. D., Moore, K. A., Boast, S., Goff, S. P., and Lemischka, I. R. (1995) Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 3, 147–161.PubMedCrossRefGoogle Scholar
  103. 103.
    Wang, J. H., Nichogiannopoulou, A., Wu, L., Sun, L., Sharpe, A. H., Bigby, M., and Georgopoulos, K. (1996) Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity 5, 537–549.Google Scholar
  104. 104.
    Bernstein, A. (1993) Receptor tyrosine kinases and the control of hematopoiesis. Sem. Dev. Biol. 4, 351–358.CrossRefGoogle Scholar
  105. 105.
    Witte, O. N. (1990) Steel locus defines new multipotent growth factor. Cell 63, 5–6.PubMedCrossRefGoogle Scholar
  106. 106.
    Hassan, H. T. and Zander, A. (1996) Stem cell factor as a survival and growth factor in human normal and malignant hematopoiesis. Acta. Haematol. 95, 257–262.PubMedCrossRefGoogle Scholar
  107. 107.
    Williams, D. A., Rios, M., Stephens, C., and Patel, V. P. (1991) Fibronectin and VLA-4 in haematopoietic stem cell-microenvironment interactions. Nature 352, 438–441.PubMedCrossRefGoogle Scholar
  108. 108.
    Arroyo, A. G., Yang, J. T., Rayburn, H., and Hynes, R. O. (1996) Differential requirements for alpha4 integrins during fetal and adult hematopoiesis. Cell 85, 997–1008.Google Scholar
  109. 109.
    Fassler, R. and Meyer, M. (1995) Consequences of lack of beta 1 integrin gene expression in mice. Genes Dev. 9, 1896–1908.PubMedCrossRefGoogle Scholar
  110. 110.
    Stephens, L. E., Sutherland, A. E., Klimanskaya, I. V., Andrieux, A., Meneses, J., Pedersen, R. A., and Damsky, C. H. (1995) Deletion of beta 1 integrins in mice results in inner cell mass failure and peri-implantation lethality. Genes Dev. 9, 1883–1895.PubMedCrossRefGoogle Scholar
  111. 111.
    Hirsch, E., Iglesias, A., Potocnik, A. J., Hartmann, U., and Fassler, R. (1996) Impaired migration but not differentiation of haematopoietic stem cells in the absence of beta1 integrins. Nature 380, 171–175.PubMedCrossRefGoogle Scholar
  112. 112.
    Warren, A. J., Colledge, W. H., Carlton, M. B., Evans, M. J., Smith, A. J., and Rabbitts, T. H. (1994) The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development. Cell 78, 45–57.Google Scholar
  113. 113.
    Fujiwara, Y., Browne, C. P., Cunniff, K., Goff, S. C., and Orkin, S. H. (1996) Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA1. Proc. Natl. Acad. Sci. USA 93, 12,355–12, 358.Google Scholar
  114. 114.
    Pevny, L., Lin, C. S., D. A. V., Simon, M. C., Orkin, S. H., and Costantini, F. (1995) Development of hematopoietic cells lacking transcription factor GATA-1. Development 121, 163–172.Google Scholar
  115. 115.
    Pevny, L., Simon, M. C., Robertson, E., Klein, W. H., Tsai, S. F., D. A. V., Orkin, S. H., and Costantini, F. (1991) Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature 349, 257–260.Google Scholar
  116. 116.
    Nuez, B. Michalovich, D., Bygrave, A., Ploemacher, R., and Grosveld, F. (1995) Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene. Nature 375 316–318.Google Scholar
  117. 117.
    Perkins, A. C., Sharpe, A. H., and Orkin, S. H. (1995) Lethal beta-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF. Nature 375, 318–322.PubMedCrossRefGoogle Scholar
  118. 118.
    Lin, C. S., Lim, S. K., D’Agati, V., and Costantini, F. (1996) Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. Genes Dev. 10, 154–164.PubMedCrossRefGoogle Scholar
  119. 119.
    Wu, H., Liu, X., Jaenisch, R., and Lodish, H. F. (1995) Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 83, 59–67.PubMedCrossRefGoogle Scholar
  120. 120.
    Keller, G. M. (1995) In vitro differentiation of embryonic stem cells. Curr. Opin. Cell. Biol. 7, 862–869.PubMedCrossRefGoogle Scholar
  121. 121.
    Muller, A., and Dzierzak, E. (1993) ES cells as a model of embryonic hematopoiesis? Sem. Dev. Biol. 4, 341–350.CrossRefGoogle Scholar
  122. 122.
    Doetschman, T. C., Eistetter, H., Katz, M., Schmidt, W., and Kemler, R. (1985) The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J. Embryol. Exp. Morphol. 87, 27–45.PubMedGoogle Scholar
  123. 123.
    Nakano, T., Kodama, H., and Honjo, T. (1994) Generation of lymphohematopoietic cells from embryonic stem cells in culture. Science 265, 1098–1101.PubMedCrossRefGoogle Scholar
  124. 124.
    Kennedy, M., Firpo, M., Choi, K., Wall, C., Robertson, S., Kabrun, N., and Keller, G. (1997) A common precursor for primitive erythropoiesis and definitive haematopoiesis. Nature 386, 488–493.PubMedCrossRefGoogle Scholar
  125. 125.
    Hole, N., Graham, G. J., Menzel, U., and Ansell, J. D. (1996) A limited temporal window for the derivation of multilineage repopulating hematopoietic progenitors during embryonal stem cell differentiation in vitro. Blood 88, 1266–1276.Google Scholar
  126. 126.
    Muller, A. M. and Dzierzak, E. A. (1993) ES cells have only a limited lymphopoietic potential after adoptive transfer into mouse recipients. Development 118, 1343–1351.PubMedGoogle Scholar
  127. 127.
    Peault, B. (1996) Hematopoietic stem cell emergence in embryonic life: developmental hematology revisited. J. Hematother. 5, 369–78.PubMedCrossRefGoogle Scholar
  128. 128.
    Migliaccio, G., Migliaccio, A. R., Petti, S., Mavilio, F., Russo, G., Lazzaro, D., Testa, U., Marinucci, M., and Peschle, C. (1986) Human embryonic hemopoiesis. Kinetics of progenitors and precursors underlying the yolk sac-liver transition. J. Clin. Invest. 78, 51–60.PubMedCrossRefGoogle Scholar
  129. 129.
    Haynes, B. F., Martin, M. E., Kay, H. H., and Kurtzberg, J. (1988) Early events in human T cell ontogeny. Phenotypic characterization and immunohistologic localization of T cell precursors in early human fetal tissues [published erratum appears in J Exp Med 1989 Feb 1;169(2):603]. J. Exp. Med. 168, 1061–1080.Google Scholar
  130. 130.
    Lobach, D. F., Hensley, L. L., Ho, W., and Haynes, B. F. (1985) Human T cell antigen expression during the early stages of fetal thymic maturation. J. Immunol. 135, 1752–1759.PubMedGoogle Scholar
  131. 131.
    Charbord, P., Tavian, M., Humeau, L., and Peault, B. (1996) Early ontogeny of the human marrow from long bones: an immunohistochemical study of hematopoiesis and its microenvi-ronment [see comments]. Blood 87, 4109–4119.PubMedGoogle Scholar
  132. 132.
    Huyhn, A., Dommergues, M., Izac, B., Croisille, L., Katz, A., Vainchenker, W., and Coulombel, L. (1995) Characterization of hematopoietic progenitors from human yolk sacs and embryos. Blood 86, 4474–4485.PubMedGoogle Scholar
  133. 133.
    Tavian, M., Coulombel, L., Luton, D., Clemente, H. S., F. Dieterlen-Lievre, and Peault, B. (1996) Aorta-associated CD34+ hematopoietic cells in the early human embryo. Blood 87, 67–72.PubMedGoogle Scholar
  134. 134.
    Garcia-Porrero, J. A., Godin, I. E., and Dieterlen-Lievre, F. (1995) Potential intraembryonic hemogenic sites at pre-liver stages in the mouse. Anat. Embryol. (Berl) 192, 425–435.Google Scholar

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© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Elaine Dzierzak
  • Alexander Medvinsky

There are no affiliations available

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