Hematopoiesis and the Red Blood Cell

  • M. J. Koury
  • C. Bauer


The cellular components of the blood include several distinctly different types of cells. Each cell type, in turn, has specific functions. Erythrocytes, which are involved in the transport of the respiratory gases, oxygen and carbon dioxide, are anucleate, biconcave discoid cells filled with hemoglobin. Granulocytes and monocytes, which play key roles in inflammation and phagocytosis, are highly mobile outside of the blood vessels and possess granules of degradative enzymes. Platelets provide hemostasis through their abilities to adhere, aggregate, and provide a surface for coagulation reactions. Platelets are very small, anucleate cells which contain localized concentrations of molecules required for hemostasis. Lymphocytes mediate immunity through immunoglobulin production by B-lymphocytes and cellular immunity through the programming of mature T-lymphocytes. A histological overview of these diverse cell types is given in Fig. 84.1.


Hematopoietic Stem Cell Hematopoietic Progenitor Cell Erythroid Differentiation Hematopoietic Growth Factor Erythroid Progenitor Cell 
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.
    Dexter TM, Allen TD, Lajtha LG (1977) Conditions controlling the proliferation of haemopoietic stem cells in vitro. J Cell Physiol 91:335–344PubMedCrossRefGoogle Scholar
  2. 2.
    Gartner S, Kaplan HS (1980) Long-term culture of human bone marrow cells. Proc Natl Acad Sci U S A 77:4756–4759PubMedCrossRefGoogle Scholar
  3. 3.
    Russell ES (1979) Hereditary anemias of the mouse: a review for geneticists. Adv Genet 20:357–459PubMedCrossRefGoogle Scholar
  4. 4.
    Chabot B, Stephenson DA, Chapman VM, Besmer P, Bernstein A (1988) The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus. Nature 335:88–89PubMedCrossRefGoogle Scholar
  5. 5.
    Geissler EN, Ryan MA, Housman DE (1988) The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. Cell 55:185–192PubMedCrossRefGoogle Scholar
  6. 6.
    Copeland NG, Gilbert DJ, Cho BC, Donovan PJ, Jenkins NA, Cosman D, Anderson D, Lyman SD, Williams DE (1990) Mast cell growth factor maps near the steel locus on mouse chromosome 10 and is deleted in a number of steel alleles. Cell 63:175–183PubMedCrossRefGoogle Scholar
  7. 7.
    Huang E, Nocka K, Beier DR, Chu T-Y, Buck J, Lahm H-W, Wellner D, Leder P, Besmer P (1990) The hematopoietic growth factor KL is encoded by the sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell 63:225–233PubMedCrossRefGoogle Scholar
  8. 8.
    Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin FH, Atkins HL, Hsu R-Y, Birkett NC, Okino KH, Murdock DC, Jacobsen FW, Langley KE, Smith KA, Takeishi T, Cattanach BM, Galli SJ, Suggs SV (1990) Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell 63:213–224PubMedCrossRefGoogle Scholar
  9. 9.
    Tavassoli M, Hardy CL (1990) Molecular basis of homing of intravenously transplanted stem cells to the marrow. Blood 76:1059–1070PubMedGoogle Scholar
  10. 10.
    Patel VP, Lodish HF (1986) The fibronectin receptor on mammalian erythroid precursor cells: characterization and developmental regulation. J Cell Biol 102:449–456PubMedCrossRefGoogle Scholar
  11. 11.
    Campbell AD, Long MW, Wicha MS (1987) Haemonectin, a bone marrow adhesion protein specific for cells of granulocyte lineage. Nature 329:744–746PubMedCrossRefGoogle Scholar
  12. 12.
    Gordon MY, Riley GP, Watt SM, Greaves ME (1987) Compartmentalization of a haematopoietic growth factor (GM-CSF) by glycosaminoglycans in the bone marrow microenvironment. Nature 326:403–405PubMedCrossRefGoogle Scholar
  13. 13.
    Roberts R, Gallagher J, Spooncer E, Allen TD, Bloomfield F, Dexter TM (1988) Heparan sulphate bound growth factors: a mechanism for stromal cell mediated haemopoiesis. Nature 332:376–378PubMedCrossRefGoogle Scholar
  14. 14.
    Boggs DR, Boggs SS, Saxe DG, Gress LA, Canfield DR (1982) Hematopoietic stem cells with high proliferative potential.. J Clin Invest 70:242–253PubMedCrossRefGoogle Scholar
  15. 15.
    Jones RJ, Sharkis S J, Celano P, Colvin OM, Rowley SD, Sensenbrenner LL (1987) Progenitor cell assays predict hematopoietic reconstitution after syngeneic transplantation in mice. Blood 70:1186–1192PubMedGoogle Scholar
  16. 16.
    Harrison DE, Astle CM, Stone M (1989) Numbers and functions of transplantable primitive immunohemopoietic stem cells: effects of age. J Immunol 142:3833–3840PubMedGoogle Scholar
  17. 17.
    Till JE, McCulloch EA (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14:213–222PubMedCrossRefGoogle Scholar
  18. 18.
    Siminovitch L, McCulloch EA, Till JE (1963) The distribution of colony-forming cells among spleen colonies. J Cell Comp Physiol 62:327–336CrossRefGoogle Scholar
  19. 19.
    Wu AM, Till JE, Siminovitch L, McCulloch EA (1967) A cyto-logical study of the capacity for differentiation of normal hemopoietic colony-forming cells. J Cell Physiol 69:177–184PubMedCrossRefGoogle Scholar
  20. 20.
    Curry JL, Trentin JJ (1967) Hematopoietic spleen colony studies. I. Growth and differentiation. Dev Biol 15:395–400PubMedCrossRefGoogle Scholar
  21. 21.
    Magli MC, Iscove NN, Odartchenko N (1982) Transient nature of early haematopoietic spleen colonies. Nature 295:527–529PubMedCrossRefGoogle Scholar
  22. 22.
    Jones RJ, Wagner JE, Celano P, Zicha MS, Sharkis SJ (1990) Separation of pluripotent hematopoietic stem cells from spleen colony forming cells. Nature 347:188–189PubMedCrossRefGoogle Scholar
  23. 23.
    Harrison DE (1980) Competitive repopulation: a new assay for long-term stem cell functional capacity. Blood 55:77–81PubMedGoogle Scholar
  24. 24.
    Dick JE, Magli MC, Huszar D, Phillips RA, Bernstein A (1985) Introduction of a selectable gene into primitive stem cells capable of long-term reconstitution of the hemopoietic system of W/W v mice. Cell 42:71–79PubMedCrossRefGoogle Scholar
  25. 25.
    Keller G, Paige C, Gilboa E, Wagner EF (1985) Expression of a foreign gene in myeloid and lymphoid cells derived from multipotent haematopoietic precursors. Nature 318:149–154PubMedCrossRefGoogle Scholar
  26. 26.
    Lemischka IR, Raulet DH, Mulligan RC (1986) Developmental potential and dynamic behavior of hematopoietic stem cells. Cell 45:917–927PubMedCrossRefGoogle Scholar
  27. 27.
    Mintz B, Anthony K, Litwin S (1984) Monoclonal derivation of mouse myeloid and lymphoid lineages from totipotent hematopoietic stem cells experimentally engrafted in fetal hosts. Proc Natl Acad Sci USA 81:7835–7839PubMedCrossRefGoogle Scholar
  28. 28.
    Micklem HS, Lennon JE, Ansell JD, Gray RA (1987) Numbers and dispersion of repopulating hematopoietic cell clones in radiation chimeras as functions of injected cell dose. Exp Hematol 15:251–257PubMedGoogle Scholar
  29. 29.
    Harrison DE, Astle CM, Lerner C (1988) Number and continuous proliferative pattern of transplanted primitive immunohematopoietic stem cells. Proc Natl Acad Sci USA 85:822–826PubMedCrossRefGoogle Scholar
  30. 30.
    Jordan CT, Lemischka IR (1990) Clonal and systemic analysis of long-term hematopoiesis in the mouse. Genes Dev 4:220–232PubMedCrossRefGoogle Scholar
  31. 31.
    Keller G, Snodgrass R (1990) Life span of multipotential hematopoietic stem cells in vivo. J Exp Med 171:1407–1418PubMedCrossRefGoogle Scholar
  32. 32.
    Capel B, Hawley RG, Mintz B (1990) Long- and short-lived murine hematopoietic stem cell clones individually identified with retroviral integration markers. Blood 75:2267–2270PubMedGoogle Scholar
  33. 33.
    Lerner C, Harrison DE (1990) 5-Fluorouracil spares hemopoietic stem cells responsible for long term repopulation. Exp Hematol 18:114–118PubMedGoogle Scholar
  34. 34.
    Spangrude GJ, Johnson GR (1990) Resting and activated subsets of mouse multipotent hematopoietic stem cells. Proc Natl Acad Sci USA 87:7433–7437PubMedCrossRefGoogle Scholar
  35. 35.
    Spangrude GJ, Heimfeld S, Weissman IL (1988) Purification and characterization of mouse hematopoietic stem cells. Science 241:58–62PubMedCrossRefGoogle Scholar
  36. 36.
    Koury MJ, Bondurant MC (1993) Prevention of brogrammed death in hematopoietic progenitor cells by hematopoietic growth factors. News Physiol Sci 8:170–174Google Scholar
  37. 37.
    Trentin JJ (1970) Influence of hematopoietic organ stroma (hematopoietic inductive microenvironments) on stem cell differentiation. In: Gordon A (ed) Regulation of hematopoiesis. Appleton-Century-Crofts, New York, pp 161–168Google Scholar
  38. 38.
    Goldwasser E (1975) Erythropoietin and differentiation of red blood cells. Fed Proc 34:2285–2292PubMedGoogle Scholar
  39. 39.
    Till JE, McCulloch EA, Siminovitch L (1964) A stochastic model of stem cell proliferation, based on the growth of spleen colony forming cells. Proc Natl Acad Sci USA 51:29–36PubMedCrossRefGoogle Scholar
  40. 40.
    Nakahata T, Gross AJ, Ogawa M (1982) A stochastic model of self-renewal and commitment to differentiation of the primitive hemopoietic stem cells in culture. J Cell Physiol 113:455–458PubMedCrossRefGoogle Scholar
  41. 41.
    Leary AG, Ogawa M, Strauss LC, Civin CI (1984) Single cell origin of multilineage colonies in culture: evidence that differentiation of multipotent progenitors and restriction of proliferative potential of monopotent progenitors are stochastic processes. J Clin Invest 74:2193–2197PubMedCrossRefGoogle Scholar
  42. 42.
    Hodgson GS, Bradley TR (1979) Properties of haematopoietic stem cells surviving 5-fluorouracil treatment: evidence for a pre-CFU-S cell? Nature 281:381–382PubMedCrossRefGoogle Scholar
  43. 43.
    Nakahata T, Ogawa M (1982) Identification in culture of a class of hemopoietic colony-forming units with extensive capability to self-renew and generate multipotential hemopoietic colonies. Proc Natl Acad Sci U S A 79:3843–3847PubMedCrossRefGoogle Scholar
  44. 44.
    Pragnell IB, Wright EG, Lorimore SA, Adam J, Rosendaal M, DeLamarter JF, Freshney M, Eckmann L, Sproul A, Wilkie N (1988) The effect of stem cell proliferation regulatiors demonstrated with an in vitro assay. Blood 72:196–201PubMedGoogle Scholar
  45. 45.
    Lapidot T, Pflumio F, Doedens M, Murdoch B, Williams DE, Dick JE (1992) Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice. Science 255:1137–1141PubMedCrossRefGoogle Scholar
  46. 46.
    Moore MAS, Williams N, Metcalf D (1972) Purification and characterization of the in vitro colony forming cells in monkey hemopoietic tissue. J Cell Physiol 79:283–292PubMedCrossRefGoogle Scholar
  47. 47.
    Metcalf D (1991) Control of granulocytes and macrophages: molecular, cellular, and clinical aspects. Science 254:529–533PubMedCrossRefGoogle Scholar
  48. 48.
    Eaves AC, Eaves CJ (1984) Erythropoiesis in culture. Clin Haematol 13:371–391PubMedGoogle Scholar
  49. 49.
    Hoffman R (1989) Regulation of megakaryocytopoiesis. Blood 74:1196–1212PubMedGoogle Scholar
  50. 50.
    Bazan JF (1990) Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci USA 87:6934–6938PubMedCrossRefGoogle Scholar
  51. 51.
    Bazan JF (1990) Haemopoietic receptors and helical cytokines. Immunol Today 11:350–354PubMedCrossRefGoogle Scholar
  52. 52.
    Manavalan P, Swope DL, Withy RM (1992) Sequence and structural relationships in the cytokine family. J Prot Chem 11:321–331CrossRefGoogle Scholar
  53. 53.
    Kitamura T, Sato N, Arai K, Miyajima A (1991) Expression cloning of the human IL-3 receptor cDNA reveals a shared β subunit for human IL-3 and GM-CSF receptors. Cell 66:1165–1174PubMedCrossRefGoogle Scholar
  54. 54.
    Tavernier J, Devos R, Cornelis S, Tuypens T, Van der Heyden J, Fiers W, Plaetinck G (1991) A human high affinity interleukin-5 receptor (IL5R) is composed of an IL5-specific a chain and a β chain shared with the receptor for GM-CSF. Cell 66:1175–1184PubMedCrossRefGoogle Scholar
  55. 55.
    Gearing DP, Comeau MR, Friend DJ, Gimpel SD, Thut CJ, McGourty J, Brasher KK, King JA, Gillis S, Mosley B, Ziegler SF, Cosman D (1992) The IL-6 signal transducer, gpl30: an oncostatin M receptor and affinity converter for the LIF receptor. Science 255:1434–1437PubMedCrossRefGoogle Scholar
  56. 56.
    Sherr CJ, Rettenmier CW, Sacca R, Roussel MF, Look AT, Stanley ER (1985) The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1. Cell 41:665–676PubMedCrossRefGoogle Scholar
  57. 57.
    Matsushime H, Roussel MF, Ashmun RA, Sherr CJ (1991) Colony-stimulating factor 1 regulates novel cyclins during the Gl phase of the cell cycle. Cell 65:701–713PubMedCrossRefGoogle Scholar
  58. 58.
    Oster W, Lindemann A, Mertelsmann R, Herrmann F (1989) Granulocyte-macrophage colony-stimulating factor (CSF) and multilineage CSF recruit human monocytes to express granulocyte CSF. Blood 73:64–67PubMedGoogle Scholar
  59. 59.
    Vellenga E, Rambaldi A, Ernst TJ, Ostapovicz D, Griffin JD (1988) Independent regulation of M-CSF and G-CSF gene expression in human monocytes. Blood 71:1529–1532PubMedGoogle Scholar
  60. 60.
    Bagby GC, Segal GM (1991) Growth factors and the control of hematopoiesis. In: Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ (eds) Hematology basic principles and practice. Churchill Livingstone, New York, p 108Google Scholar
  61. 61.
    Yoshida H, Hayashi S-I, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD, Nishikawa S-I (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony-stimulating factor gene. Nature 345:442–444PubMedCrossRefGoogle Scholar
  62. 62.
    Wiktor-Jedrzejczak W, Bartocci A, Ferrante W, Ahmed-Ansari A, Sell KW, Pollard JW, Stanley ER (1990) Total absence of colony-stimulating factor 1 in the macrophage-déficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci USA 87:4828–4832PubMedCrossRefGoogle Scholar
  63. 63.
    Burstein SA, Adamson JW, Erb SK, Harker LA (1981) Megakaryocytopoiesis in the mouse: response to varying platelet demand. J Cell Physiol 109:333–341PubMedCrossRefGoogle Scholar
  64. 64.
    Williams N, Eger RR, Jackson HM, Nelson DJ (1982) Two-factor requirement for murine megakaryocyte colony formation. J Cell Physiol 110:101–104PubMedCrossRefGoogle Scholar
  65. 65.
    Clark MR (1988) Senescence of red blood cells: progress and problems. Physiol Rev 68:503–554PubMedGoogle Scholar
  66. 66.
    Lutz HU (1990) Erythrocyte clearance. In: Harris JR (ed) Blood cell biochem, vol I. Plenum, New York, pp 81–120Google Scholar
  67. 67.
    Kay MMB (1975) Mechanism of removal senescent cells by human macrophages in situ. Proc Natl Acad Sci USA 72:3521–3525PubMedCrossRefGoogle Scholar
  68. 68.
    Singer JA, Jennings LK, Jackson C, Doctker ME, Morrison M, Walker WS (1986) Erythrocyte homeostasis: antibody-mediated recognition of the senescent state by macrophages. Proc Natl Acad Sci USA 83:5498–5501PubMedCrossRefGoogle Scholar
  69. 69.
    Turrini F, Arese P, Yuan J, Low PS (1991) Clustering of integral membrane proteins of the human erythrocyte membrane stimulates autologous IgG binding, complement deposition, and phagocytosis. J Biol Chem 266:23611–23617PubMedGoogle Scholar
  70. 70.
    Axelrad AA, McLeod DL, Shreeve MM, Heath DS (1973) Properties of cells that produce erythrocytic colonies in vitro. In: Robinson WA (ed) Proceedings of the 2nd international workshop on hemopoiesis in culture. DHEW Publ NIH 74–205, pp 226–234Google Scholar
  71. 71.
    Stephenson JR, Axelrad AA, McLeod DL, Shreeve MM (1971) Induction of colonies of hemoglobin-synthesizing cells by erythropoetin in vitro. Proc Natl Acad Sci USA 68:1542–1546PubMedCrossRefGoogle Scholar
  72. 72.
    Gregory CJ (1976) Erythropoietin sensitivity as a differentiation marker in the hemopoietic system: studies of three erythropoietic colony responses in culture. J Cell Physiol 89:289–302PubMedCrossRefGoogle Scholar
  73. 73.
    Gregory CJ, Eaves AC (1977) Human marrow cells capable of erythropoietic differentiaiton in vitro: definition of three erythroid colony responses. Blood 49:855–864PubMedGoogle Scholar
  74. 74.
    Metcalf D, Johnson GR, Burgess AW (1980) Direct stimulation by purified GM-CSF of the proliferation of multipotential and erythroid precursor cells. Blood 55:138–147PubMedGoogle Scholar
  75. 75.
    Emerson SG, Yang YC, Clark SC, Long MW (1988) Human recombinant granulocyte-macrophage colony stimulating factor and interleukin-3 have overlapping but distinct hematopoietic activities. J Clin Invest 82:1282–1287PubMedCrossRefGoogle Scholar
  76. 76.
    Sonoda Y, Yang YC, Wong GG, Clark SC, Ogawa M (1988) Erythroid burst-promoting activity of purified recombinant human GM-CSF and interleukin-3: studies with anti-GM-CSF and anti-IL-3 sera and studies in serum-free cultures. Blood 72:1381–1386PubMedGoogle Scholar
  77. 77.
    Dai CH, Krantz SB, Zsebo KM (1991) Human burst-forming units-erythroid need direct interaction with stem cell factor for further development. Blood 78:2493–2497PubMedGoogle Scholar
  78. 78.
    Iscove NN (1977) The role of erythropoietin in regulation of population size and cell cycling of early and late erythroid precursors in mouse bone marrow. Cell Tissue Kinet 10:323–334PubMedGoogle Scholar
  79. 79.
    Hara H, Ogawa M (1977) Erythropoietic precursors in mice under erythropoietic stimulation and suppression. Exp Hematol 5:141–148PubMedGoogle Scholar
  80. 80.
    Gregory CJ, Eaves AC (1978) Three stages of erythropoietic progenitor cell differentiation distinguished by a number of physical and biologic properties. Blood 51:527–537PubMedGoogle Scholar
  81. 81.
    Sieff CA, Emerson SG, Mufson A, Gesner TG, Nathan DG (1986) Dependence of highly enriched human bone marrow progenitors on hematopoietic growth factors and their response to recombinant erythropoietin. J Clin Invest 77:74–81PubMedCrossRefGoogle Scholar
  82. 82.
    Dessypris EN, Krantz SB (1984) Effect of pure erythropoetin on DNA synthesis by human marrow day 15 erythroid burst-forming units in short-term liquid culture. Br J Haematol 56:295–306PubMedCrossRefGoogle Scholar
  83. 83.
    Emerson SG, Thomas S, Ferrara JL, Greenstein JL (1989) Developmental regulation of erythropoiesis by hematopoietic growth factors: analysis on populations of BFU-E from bone marrow, peripheral blood, and fetal liver. Blood 74:49–55PubMedGoogle Scholar
  84. 84.
    Valtieri M, Gabbianelli M, Pelosi E, Bassano E, Petti S, Russo G, Testa U, Peschle C (1989) Erythropoietin alone induces erythroid burst formation by human embryonic but not adult BFU-E in unicellular serum-free culture. Blood 74:460–470PubMedGoogle Scholar
  85. 85.
    Sawyer ST (1990) Receptors for erythropoietin. Distribution, structure, and role in receptor-mediated endocytosis in erythroid cells. In: Harris JR (ed) Blood cell biochemistry, vol I. Plenum, New York, pp 365–402Google Scholar
  86. 86.
    Landschulz KT, Noyes AN, Rogers O, Boyer SH (1989) Erythropoietin receptors on murine erythroid colony-forming units: natural history. Blood 73:1476–1486PubMedGoogle Scholar
  87. 87.
    Sawada K, Krantz SB, Dai CH, Koury ST, Horn ST, Glick AD, Civin CI (1990) Purification of human blood burst-forming units-erythroid and demonstration of the evolution of erythropoietin receptors. J Cell Physiol 142:219–230PubMedCrossRefGoogle Scholar
  88. 88.
    Krantz SB (1991) Erythropoietin. Blood 77:419–434Google Scholar
  89. 89.
    Spivak JL (1992) The mechanism of action of erythropoietin: erythroid cell response. In: Fisher Jw (ed) Biochemical pharmacology of blood and blood forming organs. Springa, Berin Heidelbery New York, pp 49–114 (Handbook of experimental pharmacology, vol 101)CrossRefGoogle Scholar
  90. 90.
    Koury MJ, Bondurant MC (1992) The molecular mechanism of erythropoietin action. Eur J Biochem 210:649–663PubMedCrossRefGoogle Scholar
  91. 91.
    Fibi MR, Stuber W, Hintz-Obertreis P, Luben G, Krumwieh D, Siebold B, Zettlemeissl G, Kupper HA (1991) Evidence for the location of the receptor-binding site of human erythropoietin at the carboxy-terminal domain. Blood 77:1203–1210PubMedGoogle Scholar
  92. 92.
    Dordal MS, Wang FF, Goldwasser E (1985) The role of carbohydrate in erythropoietin action. Endocrinology 116:2293–2299PubMedCrossRefGoogle Scholar
  93. 93.
    Takeuchi M, Inoue N, Strickland TW, Kubota M, Wada M, Shimizu R, Hoshi S, Kozutsumi H, Takasaki S, Kobata A (1989) Relationship between sugar chain structure and biological activity of recombinant human erythropoietin produced in Chinese hamster ovary cells. Proc Natl Acad Sci USA 86:7819–7822PubMedCrossRefGoogle Scholar
  94. 94.
    Wasley LC, Timony G, Murtha P, Stoudemire J, Dorner AJ, Caro J, Krieger M, Kaufman RJ (1991) The importance of N-and O-linked oligosaccharides for the biosynthesis and in vitro and in vivo biologic activities of erythropoietin. Blood 77:2624–2632PubMedGoogle Scholar
  95. 95.
    Yamaguchi K, Akai K, Kawanishi G, Ueda M, Masuda S, Sasaki R (1991) Effects of site-directed removal of N-glycosylation sites in human erythropoietin on its production and biological properties. J Biol Chem 266:20434–20439PubMedGoogle Scholar
  96. 96.
    Jacobs K, Shoemaker C, Rudersdorf R, Neill SD, Kaufman RJ, Mufson A, Seehra J, Jones SS, Hewick R, Fritsch EF, Kawakita M, Shimizu T, Miyake T (1985) Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 313:806–810PubMedCrossRefGoogle Scholar
  97. 97.
    Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z, Badrawi SM, Lai PH, Goldwasser E (1985) Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA 82:7580–7584PubMedCrossRefGoogle Scholar
  98. 98.
    Schuster SJ, Badiavas EV, Gosta-Giomi P, Weinmann R, Erslev A J, Caro J (1989) Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure. Blood 73:13–16PubMedGoogle Scholar
  99. 99.
    Goldberg MA, Gaut CC, Bunn HF (1991) Erythropoietin mRNA levels are governed by both the rate of gene transcription and posttranscriptional events. Blood 77:271–277PubMedGoogle Scholar
  100. 100.
    Jacobson LO, Goldwasser E, Fried W, Plazak L (1957) Role of the kidney in erythropoiesis. Nature 179:633–634PubMedCrossRefGoogle Scholar
  101. 101.
    Fried W (1972) The liver as a source of extrarenal erythropoietin production. Blood 40:671–677PubMedGoogle Scholar
  102. 102.
    Bondurant MC, Koury MJ (1986) Anemia induces accumulation of erythropoietin mRNA in the kidney and liver. Mol Cell Biol 6:2731–2733PubMedGoogle Scholar
  103. 103.
    Zanjani ED, Poster J, Burlington H (1977) Liver as the primary site of erythropoietin production in the fetus. J Lab Clin Med 89:640–644PubMedGoogle Scholar
  104. 104.
    Koury MJ, Bondurant MC, Graber SE, Sawyer ST (1988) Erythropoietin messenger RNA levels in developing mice and transfer of 125I-erythropoietin by the placenta. J Clin Invest 82:154–159PubMedCrossRefGoogle Scholar
  105. 105.
    Eckardt KU, Ratcliffe PJ, Tan CC, Bauer C, Kurtz A (1992) Age-dependent expression of the erythropoietin gene in rat liver and kidneys. J Clin Invest 89:753–760PubMedCrossRefGoogle Scholar
  106. 106.
    Ratcliffe PJ, Jones RW, Phillips RE, Nicholls LG, Bell JI (1990) Oxygen-dependent modulation of erythropoietin mRNA levels. J Exp Med 172:657–660PubMedCrossRefGoogle Scholar
  107. 107.
    Pagel H, Jelkmann W, Weiss CH (1991) Isolated serum-free perfused rat kidneys release immunoreactive erythropoietin in response to hypoxia. Endocrinology 128:2633–2638PubMedCrossRefGoogle Scholar
  108. 108.
    Scholz H, Schurek H J, Eckardt HU, Kurtz A, Bauer C (1991) Oxygen dependent erythropoietin production by the isolated perfused rat kidney. Pflugers Arch 418:228–233PubMedCrossRefGoogle Scholar
  109. 109.
    Goldberg MA, Glass GA, Cunningham JM, Bunn HF (1987) The regulated expression of erythropoietin by two human hepatoma cell lines. Proc Natl Acad Sci USA 84:7972–7976PubMedCrossRefGoogle Scholar
  110. 110.
    Schuster SJ, Wilson JH, Erslev AJ, Caro J (1987) Physiologic regulation and tissue localization of renal erythropoietin messenger RNA. Blood 70:316–318PubMedGoogle Scholar
  111. 111.
    Beck I, Ramirez S, Weinmann R, Caro J (1991) Enhancer element at the 3’-flanking region controls transcriptional response to hypoxia in the human erythropoietin gene. J Biol Chem 266:15563–15566PubMedGoogle Scholar
  112. 112.
    Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE (1991) Hypoxia-inducible nuclear factors bind to an enhancer element located 3’ to the human erythropoietin gene. Proc Natl Acad Sci USA 88:5680–5684PubMedCrossRefGoogle Scholar
  113. 113.
    Pugh CW, Tan CC, Jones RW, Ratcliffe PJ (1991) Functional analysis of an oxygen-regulated transcriptional enhancer 3’ to the mouse erythropoietin gene. Proc Natl Acad Sci USA 88:10553–10557PubMedCrossRefGoogle Scholar
  114. 114.
    Goldberg MA, Dunning SP, Bunn HF (1988) Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. Science 242:1412–1415PubMedCrossRefGoogle Scholar
  115. 115.
    Koury ST, Bondurant MC, Koury MJ (1988) Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood 71:524–527PubMedGoogle Scholar
  116. 116.
    Lacombe C, DaSilva JL, Bruneval P, Fournier JG, Wendling F, Casadevall N, Camilleri JP, Bariety J, Varet B, Tambourin P (1988) Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney. J Clin Invest 81:620–623CrossRefGoogle Scholar
  117. 117.
    Koury ST, Bondurant MC, Koury MJ, Semenza GL (1991) Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood 77:2497–2503PubMedGoogle Scholar
  118. 118.
    Koury ST, Koury MJ, Bondurant MC, Caro J, Graber SE (1989) Quantitation of erythropoietin-producing cells in the kidneys of mice by in situ hybridization: correlation with hematocrit, renal erythropoietin messenger RNA and serum erythropoietin concentration. Blood 74:645–651PubMedGoogle Scholar
  119. 119.
    Erslev AJ (1991) Erythropoietin. N Engl J Med 324:1339–1344PubMedCrossRefGoogle Scholar
  120. 120.
    Sawyer ST, Krantz SB, Goldwasser E (1987) Binding and receptor-mediated endocytosis of erythropoietin in Friend virus infected erythroid cells. J Biol Chem 262:5554–5562PubMedGoogle Scholar
  121. 121.
    D’Andrea AD, Lodish HF, Wong G (1989) Expression cloning of the murine erythropoietin receptor. Cell 57:277–285PubMedCrossRefGoogle Scholar
  122. 122.
    Miura O, D’Andrea A, Kabat D, Ihle JN (1991) Induction of tyrosine phosphorylation by the erythropoietin receptor correlates with mitogenesis. Mol Cell Biol 11:4895–4902PubMedGoogle Scholar
  123. 123.
    Dusanter-Fourt I, Casadevall N, Lacombe C, Müller O, Billat C, Fischer S, Mayeux P (1992) Erythropoietin induces the tyrosine phosphorylation of its own receptor in human erythropoietin-responsive cells. I Biol Chem 267:10670–10675Google Scholar
  124. 124.
    Sawyer ST (1989) The two proteins of the erythropoietin receptor are structurally similar. J Biol Chem 264:13343–13347PubMedGoogle Scholar
  125. 125.
    Mayeux P, Lacombe C, Casadevall N, Chretien S, Dusanter I, Gisselbrecht S (1991) Structure of the murine erythropoietin receptor complex characterization of the erythropoietin cross-linked proteins. J Biol Chem 266:23380–23385PubMedGoogle Scholar
  126. 126.
    Yoshimura A, Longmore G, Lodish HF (1990) Point mutation in the exoplasmic domain of the erythropoietin receptor resulting in hormone-independent activation and tumorigenicity. Nature 348:647–649PubMedCrossRefGoogle Scholar
  127. 127.
    D’Andrea A, Yoshimura A, Youssoufian H, Zon LI, Koo J-W, Lodish HF (1991) The cytoplasmic region of the erythropoietin receptor contains nonoverlapping positive and negative growth-regulatory domains. Mol Cell Biol 11:1980–1987PubMedGoogle Scholar
  128. 128.
    Carroll MP, Spivak JL, McMahon M, Welch N, Rapp UR, May WS (1991) Erythropoietin induces raf-1 activation and raf-1 is required for erythropoietin-mediated proliferation. J Biol Chem 266:14964–14969PubMedGoogle Scholar
  129. 129.
    Evans TM, Reitman M, Felsenfeld G (1988) An erythrocyte-specific DNA-binding factor recognizes a regulatory sequence common to all chicken globin genes. Proc Natl Acad Sci USA 85:5976–5980PubMedCrossRefGoogle Scholar
  130. 130.
    Wall L, deBoer E, Grosveld F (1988) The human beta-globin gene 3’ enhancer contains multiple binding sites for an erythroid-specific protein. Genes Dev 2:1089–1100PubMedCrossRefGoogle Scholar
  131. 131.
    Martin DIK, Zon LI, Mutter G, Orkin SH (1990) Expression of an erythroid transcription factor in Megakaryocyte and mast cell lineages. Nature 344:444–447PubMedCrossRefGoogle Scholar
  132. 132.
    Romeo PH, Prandini MH, Joulin V, Mignotte V, Prenant M, Vainchenker W, Marguerie G, Uzan G (1990) Megakaryocyte and erythrocytic lineages share specific transcription factors. Nature 344:447–449PubMedCrossRefGoogle Scholar
  133. 133.
    Tsuda H, Sawada T, Sakaguchi M, Kwakita M, Takatsuki K (1989) Mode of action of erythropoietin in Epo dependent murine cell line. I. Involvement of adenosine 3′:5′-cyclic monophosphate not as a second messenger but as a regulator of cell growth. Exp Hematol 17:211–217PubMedGoogle Scholar
  134. 134.
    Spivak JL, Pham T, Isaacs M, Hankins WD (1991) Erythropoietin is both a mitogen and a survival factor. Blood 77:1228–1233PubMedGoogle Scholar
  135. 135.
    Koury MJ, Bondurant MC (1990) Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. Science 248:378–381PubMedCrossRefGoogle Scholar
  136. 136.
    Wyllie AH (1987) Apoptosis: cell death in tissue regulation. J Pathol 153:313–316PubMedCrossRefGoogle Scholar
  137. 137.
    Landschulz KT, Boyer SH, Noyes AN, Rogers OC, Freiin LP (1992) Onset of erythropoietin response in murine erythroid colony-forming units: assignment to early S-phase in a specific cell generation. Blood 79:2749–2758PubMedGoogle Scholar
  138. 138.
    Nijhof W, Wierenga PK, Sahr K, Bern N, Goldwasser E (1987) Induction of globin mRNA transcription by erythropoietin in differentiating erythroid precursor cells. Exp Hematol 15:779–784PubMedGoogle Scholar
  139. 139.
    Koury MJ, Bondurant MC (1988) Maintenance by erythropoietin of viability and maturation of murine erythroid precursor cells. J Cell Physiol 137:65–74PubMedCrossRefGoogle Scholar
  140. 140.
    Koury MJ, Bondurant MC (1990) Control of red cell production: the roles of programmed cell death (apoptosis) and erythropoietin. Transfusion 30:673–674PubMedCrossRefGoogle Scholar
  141. 141.
    Iscove NN (1978) Erythropoietin-independent stimulation of early erythropoiesis in adult marrow cultures by conditioned media from lectin-stimulated mouse spleen cells. In: Golde DW, Cline MJ, Metcalfe D, Fox CF (eds) Hematopoietic cell differentiation. Academic, New York, pp 37–52Google Scholar
  142. 142.
    Del Rizzo DF, Axelrad AA (1985) Erythroid progenitor cells (CFU-E*) from Friend virus-infected mice undergo 55Fe suicide in vitro in the absence of added erythropoietin. Exp Hematol 13:1055–1061PubMedGoogle Scholar
  143. 143.
    Lipton JM, Kudisch M, Nathan DG (1981) Response of three classes of human erythroid progenitors to the absence of erythropoietin in vitro as a measure of progenitor maturity. Exp Hematol 9:1035–1041PubMedGoogle Scholar
  144. 144.
    Iscove NN, Sieber F, Winterhalter KH (1974) Eythroid colony formation in cultures of mouse and human bone marrow: analysis of the requirement for erythropoietin by gel filtration and affinity chromatography on agarose-conca-navalin A. J Cell Physiol 83:309–320PubMedCrossRefGoogle Scholar
  145. 145.
    Gregory CJ, Tepperman AD, McCulloch EA, Till JE (1974) Erythropoietic progenitors capable of colony formation in culture: Response of normal and genetically anemic W/W v mice to manipulations of the erythron. J Cell Physiol 84:1–12PubMedCrossRefGoogle Scholar
  146. 146.
    Axelrad AA (1990) Some hemopoietic negative regulators. Exp Hematol 18:143–150PubMedGoogle Scholar
  147. 147.
    Graham GJ, Pragnell IB (1990) Negative regulators of haemopoiesis — current advances. Prog Growth Factor Res 2:181–192PubMedCrossRefGoogle Scholar
  148. 148.
    Moore MAS (1991) Clinical impications of positive and negative hematopoietic stem cell regulators. Blood 78:1–19PubMedGoogle Scholar
  149. 149.
    Weiss C, Jelkmann W (1989) Functions of the blood. In: Schmidt RF, Thews G (eds) Human physiology, 2nd edn. Springer, Berlin Heidelberg New YorkGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • M. J. Koury
  • C. Bauer

There are no affiliations available

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