Factors Controlling Expansion and Maturation of Haematopoietic Progenitor Cells

  • A. L. Drayer
  • E. Vellenga
Conference paper
Part of the Developments in Hematology and Immunology book series (DIHI, volume 38)

Abstract

In cancer patients receiving high-dose chemotherapy and haematopoietic stem cell (HSC) transplantation the period of profound cytopenia generally lasts between 1 to 6 weeks, depending on the number and source of HSCs infused [1–4]. Experimental transplantation models in mice have demonstrated that long-term engraftment is supported by undifferentiated stem cells, while short-term (transient) engraftment is mediated by more differentiated progenitor cells. Therefore, supplementing stem cell transplants with ex vivo expanded progenitor cells may be an approach to accelerate the haematopoietic recovery. The principle of this cell-based therapy has been demonstrated in mice and non-human primates, although the recovery is slower than predicted from the large number of progenitors infused [5–7]. In the human setting, multiple studies have now demonstrated that the ex vivo expansion process can be used to generate large quantities of more mature progenitor cells, and a number of clinical studies have shown promising results [8–11]. During culture with cytokines, cells go through different stages of the cell cycle and the expression of cell surface adhesion molecules is altered; both factors appear to influence the capacity of stem cells to migrate through the circulation and back to a supportive haematopoietic microenvironment in the bone marrow, a process referred to as “homing”.

Keywords

Stem Cell Factor Erythroid Progenitor Cell M07e Cell Transform Growth Factor Beta Signalling Megakaryocyte Progenitor 
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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References

  1. 1.
    Beyer J, Schwella N, Zingsem J, et al. Hematopoietic rescue after high-dose chemotherapy using autologous peripheral-blood progenitor cells or bone marrow: a randomized comparison. J Clin Oncol 1995;13:1328–35.PubMedGoogle Scholar
  2. 2.
    To LB, Roberts MM, Haylock DN, et al. Comparison of haematological recovery times and supportive care requirements of autologous recovery phase peripheral blood stem cell transplants, autologous bone marrow transplants and allogeneic bone marrow transplants. Bone Marrow Transplant 1992;9:277–84.PubMedGoogle Scholar
  3. 3.
    Cairo MS, Wagner JE. Placental and/or umbilical cord blood: an alternative source of hematopoietic stem cells for transplantation. Blood 1997;90:4665–78.PubMedGoogle Scholar
  4. 4.
    Hartmann O, Le Corroller AG, Blaise D, et al. Peripheral blood stem cell and bone marrow transplantation for solid tumors and lymphomas: hematologic recovery and costs. A randomized, controlled trial. Ann Intern Med 1997; 126:600–07.PubMedGoogle Scholar
  5. 5.
    Muench MO, Firpo MT, Moore MA. Bone marrow transplantation with interleukin-1 plus kit-ligand ex vivo expanded bone marrow accelerates hematopoietic reconstitution in mice without the loss of stem cell lineage and proliferative potential. Blood 1993;81:3463–73.PubMedGoogle Scholar
  6. 6.
    Andrews RG, Briddell RA, Hill R, Gough M, McNiece IK. Engraftment of primates with G-CSF mobilized peripheral blood CD34+ progenitor cells expanded in G-CSF, SCF and MGDF decreases the duration and severity of neutropenia. Stem Cells 1999;17:210–18.PubMedCrossRefGoogle Scholar
  7. 7.
    Szilvassy SJ, Weller KP, Chen B, Juttner CA, Tsukamoto A, Hoffman R. Partially differentiated ex vivo expanded cells accelerate hematologic recovery in myeloablated mice transplanted with highly enriched long- term re-populating stem cells. Blood 1996;88:3642–53.PubMedGoogle Scholar
  8. 8.
    Paquette RL, Dergham ST, Karpf E, et al. Ex vivo expanded unselected peripheral blood: progenitor cells reduce posttransplantation neutropenia, thrombocytopenia, and anemia in patients with breast cancer. Blood 2000; 96:2385–90.PubMedGoogle Scholar
  9. 9.
    McNiece I, Jones R, Bearman SI, et al. Ex vivo expanded peripheral blood progenitor cells provide rapid neutrophil recovery after high-dose chemotherapy in patients with breast cancer. Blood 2000;96:3001–07.PubMedGoogle Scholar
  10. 10.
    Bertolini F, Battaglia M, Pedrazzoli P, et al. Megakaryocyte progenitors can be generated ex vivo and safely administered to autologous peripheral blood progenitor cell transplant recipients. Blood 1997;89:2679–88.PubMedGoogle Scholar
  11. 11.
    Reiffers J, Cailliot C, Dazey B, Attal M, Caraux J, Boiron JM. Abrogation of post-myeloablative chemotherapy neutropenia by ex-vivo expanded autologous CD34-positive cells. Lancet 1999;354:1092–93.PubMedCrossRefGoogle Scholar
  12. 12.
    Lok S, Kaushansky K, Holly RD, et al. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature 1994;369:565–68.PubMedCrossRefGoogle Scholar
  13. 13.
    Wendling F, Maraskovsky E, Debili N, et al. cMpl ligand is a humoral regulator of megakaryocytopoiesis. Nature 1994;369:571–74.PubMedCrossRefGoogle Scholar
  14. 14.
    de Sauvage FJ, Hass PE, Spencer SD, et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature 1994; 369:533–38.PubMedCrossRefGoogle Scholar
  15. 15.
    Kaushansky K, Lok S, Holly RD, et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature 1994; 369:568–71.PubMedCrossRefGoogle Scholar
  16. 16.
    Gurney AL, Carver-Moore K, de Sauvage FJ, Moore MW. Thrombocytopenia in c-mpl-deficient mice. Science 1994;265:1445–47.PubMedCrossRefGoogle Scholar
  17. 17.
    Alexander WS, Roberts AW, Nicola NA, Li R, Metcalf D. Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl. Blood 1996;87:2162–70.PubMedGoogle Scholar
  18. 18.
    Carver-Moore K, Broxmeyer HE, Luoh SM, et al. Low levels of erythroid and myeloid progenitors in thrombopoietin-and c- mpl-deficient mice. Blood 1996; 88:803–08.PubMedGoogle Scholar
  19. 19.
    de Sauvage FJ, Carver-Moore K, Luoh SM, et al. Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. J Exp Med 1996;183:651–56.PubMedCrossRefGoogle Scholar
  20. 20.
    Broudy VC, Lin NL, Kaushansky K. Thrombopoietin (c-mpl ligand) acts synergistically with erythropoietin, stem cell factor, and interleukin-11 to enhance murine megakaryocyte colony growth and increases megakaryocyte ploidy in vitro. Blood 1995;85:1719–26.PubMedGoogle Scholar
  21. 21.
    Dolzhanskiy A, Hirst J, Basch RS, Karpatkin S. Complementary and antagonistic effects of IL-3 in the early development of human megakaryocytes in culture. Br J Haematol 1998;100:415–26.PubMedCrossRefGoogle Scholar
  22. 22.
    Williams JL, Pipia GG, Datta NS, Long MW. Thrombopoietin requires additional megakaryocyte-active cytokines for optimal ex vivo expansion of megakaryocyte precursor cells. Blood 1998;91:4118–26.PubMedGoogle Scholar
  23. 23.
    Drayer AL, Smit Sibinga CT, Blom NR, de Wolf JT, Vellenga E. The in vitro effects of cytokines on expansion and migration of megakaryocyte progenitors. Br J Haematol 2000;109:776–84.PubMedCrossRefGoogle Scholar
  24. 24.
    Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med 1997; 185:111–20.PubMedCrossRefGoogle Scholar
  25. 25.
    Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 1999;283:845–48.PubMedCrossRefGoogle Scholar
  26. 26.
    Kim CH, Broxmeyer HE. In vitro behavior of hematopoietic progenitor cells under the influence of chemoattractants: stromal cell-derived factor-1, steel factor, and the bone marrow environment. Blood 1998;91:100–10.PubMedGoogle Scholar
  27. 27.
    Hovenga S, de Wolf JT, Guikema JE, et al. Autologous stem cell transplantation in multiple myeloma after VAD and EDAP courses: a high incidence of oligoclonal serum Igs post transplantation. Bone Marrow Transplant 2000;25:723–28.PubMedCrossRefGoogle Scholar
  28. 28.
    Drayer AL, Smit Sibinga CT, Esselink MT, de Wolf JT, Vellenga E. In vitro megakaryocyte expansion in patients with delayed platelet engraftment after autologous stem cell transplantation. Ann Hematol 2002;81:192–97.PubMedCrossRefGoogle Scholar
  29. 29.
    Garcia J, de Gunzburg J, Eychene A, Gisselbrecht S, Porteu F. Thrombopoi-etin-mediated sustained activation of extracellular signal- regulated kinase in UT7-Mpl cells requires both Ras-Raf-1- and Rap1-B- Raf-dependent pathways. Mol Cell Biol 2001;21:2659–70.PubMedCrossRefGoogle Scholar
  30. 30.
    Drachman JG, Kaushansky K. Structure and function of the cytokine receptor superfamily. Curr Opin Hematol 1995;2:22–28.PubMedCrossRefGoogle Scholar
  31. 31.
    Drachman JG. Millett KM, Kaushansky K. Thrombopoietin signal transduction requires functional JAK2, not TYK2. J Biol Chem 1999;274:13480–84.PubMedCrossRefGoogle Scholar
  32. 32.
    Ihle JN. The Stat family in cytokine signaling. Curr Opin Cell Biol 2001; 13:211–17.PubMedCrossRefGoogle Scholar
  33. 33.
    Alexander WS, Maurer AB, Novak U, Harrison-Smith M. Tyrosine-599 of the c-Mpl receptor is required for Shc phosphorylation and the induction of cellular differentiation. EMBO J 1996;15:6531–40.PubMedGoogle Scholar
  34. 34.
    Geddis AE, Linden HM, Kaushansky K. Thrombopoietin: a pan-hematopoietic cytokine. Cytokine Growth Factor Rev 2002;13:61–73.PubMedCrossRefGoogle Scholar
  35. 35.
    Rojnuckarin P, Miyakawa Y, Fox NE, Deou J, Daum G, Kaushansky K. The roles of phosphatidylinositol 3-kinase and protein kinase Czeta for thrombopoietin-induced mitogen-activated protein kinase activation in primary murine megakaryocytes. J Biol Chem 2001;276:41014–22.PubMedCrossRefGoogle Scholar
  36. 36.
    Miyakawa Y, Rojnuckarin P, Habib T, Kaushansky K. Thrombopoietin induces phosphoinositol 3-kinase activation through SHP2, Gab, and insulin receptor substrate proteins in BAF3 cells and primary murine megakaryocytes. J Biol Chem 2001;276:2494–502.PubMedCrossRefGoogle Scholar
  37. 37.
    Dijkers PF, Medema RH, Pals C, et al. Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIPl). Mol Cell Biol 2000;20:9138–48.PubMedCrossRefGoogle Scholar
  38. 38.
    Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999;96: 857–68.PubMedCrossRefGoogle Scholar
  39. 39.
    Rojnuckarin P, Drachman JG, Kaushansky K. Thrombopoietin-induced activation of the mitogen-activated protein kinase (MAPK) pathway in normal megakaryocytes: role in endomitosis. Blood 1999;94:1273–82.PubMedGoogle Scholar
  40. 40.
    Geddis AE, Fox NE, Kaushansky K. Phosphatidylinositol 3-kinase is necessary but not sufficient for thrombopoietin-induced proliferation in engineered Mp1-bearing cell lines as well as in primary megakaryocytic progenitors. J Biol Chem 2001;276:34473–79.PubMedCrossRefGoogle Scholar
  41. 41.
    Rouyez MC, Boucheron C, Gisselbrecht S, Dusanter-Fourt I, Porteu F. Control of thrombopoietin-induced megakaryocytic differentiation by the mitogen-activated protein kinase pathway. Mol Cell Biol 1997;17:4991–5000.PubMedGoogle Scholar
  42. 42.
    Massague J. How cells read TGF-beta signals. Nat Rev Mol Cell Biol 2000; 1:169–78.PubMedCrossRefGoogle Scholar
  43. 43.
    Fortunel NO, Hatzfeld A, Hatzfeld JA. Transforming growth factor-beta: pleiotropic role in the regulation of hematopoiesis. Blood 2000;96:2022–36.PubMedGoogle Scholar
  44. 44.
    Ishibashi T, Miller SL, Burstein SA. Type beta transforming growth factor is a potent inhibitor of murine megakaryocytopoiesis in vitro. Blood 1987;69: 1737–41.PubMedGoogle Scholar
  45. 45.
    Kuter DJ, Gminski DM, Rosenberg RD. Transforming growth factor beta inhibits megakaryocyte growth and endomitosis. Blood 1992;79:619–26.PubMedGoogle Scholar
  46. 46.
    Bruno E, Miller ME, Hoffman R. Interacting cytokines regulate in vitro human megakaryocytopoiesis. Blood 1989;73:671–77.PubMedGoogle Scholar
  47. 47.
    Waegell WO, Higley HR, Kincade PW, Dasch JR. Growth acceleration and stem cell expansion in Dexter-type cultures by neutralization of TGF-beta. Exp Hematol 1994;22:1051–57.PubMedGoogle Scholar
  48. 48.
    Wrana JL, Attisano L, Wieser R, Ventura F, Massague J. Mechanism of activation of the TGF-beta receptor. Nature 1994;370:341–47.PubMedCrossRefGoogle Scholar
  49. 49.
    Piek E, Heldin CH, ten Dijke P. Specificity, diversity, and regulation in TGF-beta superfamily signaling. FASEB J 1999;13:2105–24.PubMedGoogle Scholar
  50. 50.
    Drayer AL, Smit Sibinga CT, Esselink MT, et al. Downregulation of trombopoietin-induced proliferation, maturation and STAT5 tyrosine phosphorylation by transforming growth factor beta in megakaryoblastic M07e cells. Blood 2003;98:79a.Google Scholar
  51. 51.
    Drayer AL, Wierenga AT, Vellenga E. Transforming growth factor beta downregulates thrombopoietin-induced mitogen-activated protein kinase Erk and Erk-dependent STAT3 signalling pathways in M07e cells. Blood 2003; 100:520a.Google Scholar
  52. 52.
    Wu H, Liu X, Jaenisch R, Lodish HF. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 1995;83:59–67.PubMedCrossRefGoogle Scholar
  53. 53.
    Damen JE, Krystal G. Early events in erythropoietin-induced signaling. Exp Hematol 1996;24:1455–59.PubMedGoogle Scholar
  54. 54.
    Belegu M, Beckman B, Fisher JW. beta-Adrenergic blockade of prostaglandin E2- and D2-induced erythroid colony formation. Am J Physiol 1983;245 :C322–C327.PubMedGoogle Scholar
  55. 55.
    Fisher JW, Radtke HW, Jubiz W, Nelson PK, Burdowski A. Prostaglandins activation of erythropoietin production and erythroid progenitor cells. Exp Hematol 1980;8 (Suppl 8):65–89.PubMedGoogle Scholar
  56. 56.
    Datta MC. Prostaglandin E2 mediated effects on the synthesis of fetal and adult hemoglobin in blood erythroid bursts. Prostaglandins 1985;29:561–77.PubMedGoogle Scholar
  57. 57.
    Boer AK, Drayer AL, Rui H, Vellenga E. Prostaglandin-E2 enhances EPO-mediated STAT5 transcriptional activity by serine phosphorylation of CREB. Blood 2002;100:467–73.PubMedCrossRefGoogle Scholar
  58. 58.
    Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui AL, Kitamura T. STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells. EMBO J 1999;18:4754–65.PubMedCrossRefGoogle Scholar
  59. 59.
    Socolovsky M, Nam H, Fleming MD, Haase VH, Brugnara C, Lodish HF. Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts. Blood 2001;98:3261–73.PubMedCrossRefGoogle Scholar
  60. 60.
    Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF. Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction. Cell 1999;98:181–91.PubMedCrossRefGoogle Scholar
  61. 61.
    Liu X, Robinson GW, Gouilleux F, Groner B, Hennighausen L. Cloning and expression of Stat5 and an additional homologue (Stat5b) involved in prolactin signal transduction in mouse mammary tissue. Proc Natl Acad Sci U S A 1995;92:8831–35.PubMedCrossRefGoogle Scholar
  62. 62.
    Azam M, Erdjument-Bromage H, Kreider BL, Xia M, Quelle F, Basu R et al. Interleukin-3 signals through multiple isoforms of Stat5. EMBO J 1995; 14:1402–11.PubMedGoogle Scholar
  63. 63.
    Beuvink I, Hess D, Flotow H, Hofsteenge J, Groner B, Hynes NE. Stat5a serine phosphorylation. Serine 779 is constitutively phosphorylated in the mammary gland, and serine 725 phosphorylation influences prolactin-stimulated in vitro DNA binding activity. J Biol Chem 2000;275:10247–55.PubMedCrossRefGoogle Scholar
  64. 64.
    Yamashita H, Xu J, Erwin RA, Farrar WL, Kirken RA, Rui H. Differential control of the phosphorylation state of proline-juxtaposed serine residues Ser725 of Stat5a and Ser730 of Stat5b in prolactin- sensitive cells. J Biol Chem 1998; 273:30218–24.PubMedCrossRefGoogle Scholar
  65. 65.
    Yamashita H, Nevalainen MT, Xu J, et al. Role of serine phosphorylation of Stat5a in prolactin-stimulated beta- casein gene expression. Mol Cell Endocrinol 2001;183:151–63.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2003

Authors and Affiliations

  • A. L. Drayer
    • 1
  • E. Vellenga
    • 2
  1. 1.Sanquin Blood Bank NoordoostGroningenThe Netherlands
  2. 2.Department of HaematologyUniversity Hospital GroningenThe Netherlands

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