Chapter 3 : Growth and Differentiation Factors

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Most hematologists accept that hematopoiesis is initiated by multipotential hematopoietic stem cells. These cells are regarded as being few in number but diverse in properties and as being usually noncycling in normal health. It is well documented that, when myeloid populations are damaged by irradiation or chemotherapy, hematopoietic repopulation is initiated by such stem cells.

Citation: Metcalf† D. 2017. Growth and Differentiation Factors, p 31-41. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0004-2015
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Figure 1

When stimulated in culture, BL-CFCs can each produce large colonies containing a wide variety of committed progenitor cells in different lineages. Present in many colonies are also BL-CFCs, indicating a capacity of the initiating cells to self-generate and to sustain the continuous production of maturing progeny cells. CFU-s, colony-forming unit-spleen; E, erythroid progenitors; G, granulocyte progenitors; GM, granulocyte-macrophage progenitors; M, macrophage progenitors; Eo, eosinophil progenitors; Meg, megakaryocyte progenitors; DC, dendritic cell progenitors; T, T lymphocyte progenitors; B, B lymphocyte progenitors.

Citation: Metcalf† D. 2017. Growth and Differentiation Factors, p 31-41. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0004-2015
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Figure 2

Colony formation in 7-day cultures of C57BL mouse bone marrow cells stimulated by GM-CSF. Final concentration of GM-CSF in the 1:1 cultures was 10 ng/ml. The colony numbers ± standard deviations were derived from cultures of five different bone marrow cell populations.

Citation: Metcalf† D. 2017. Growth and Differentiation Factors, p 31-41. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0004-2015
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Figure 3

Colony formation by marrow cells from patients with acute or chronic myeloid leukemia using varying concentrations of material with colony-stimulating activity. The responsiveness of the leukemic cells to generate colonies (verified by karyotypic colony analysis) is broadly similar to that of normal human marrow cells, although some acute myeloid leukemia populations contained some cells capable of limited unstimulated proliferation.

Citation: Metcalf† D. 2017. Growth and Differentiation Factors, p 31-41. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0004-2015
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1. Sun J,, Ramos A,, Chapman B,, Johnnidis JB,, Le L,, Ho YJ,, Klein A,, Hofmann O,, Camargo FD . 2014. Clonal dynamics of native haematopoiesis. Nature 514 : 322 327.[PubMed] [CrossRef]
2. Becher B,, Schlitzer A,, Chen J,, Mair F,, Sumatoh HR,, Teng KW,, Low D,, Ruedl C,, Riccardi-Castagnoli P,, Poidinger M,, Greter M,, Ginhoux F,, Newell EW . 2014. High-dimensional analysis of the murine myeloid cell system. Nat Immunol 15 : 1181 1189.[PubMed] [CrossRef]
3. Metcalf D,, Greig KT,, de Graaf CA,, Loughran SJ,, Alexander WS,, Kauppi M,, Hyland CD,, Di Rago L,, Mifsud S . 2008. Two distinct types of murine blast colony-forming cells are multipotential hematopoietic precursors. Proc Natl Acad Sci U S A 105 : 18501 18506.[PubMed] [CrossRef]
4. Metcalf D,, Ng A,, Mifsud S,, Di Rago L . 2010. Multipotential hematopoietic blast colony-forming cells exhibit delays in self-generation and lineage commitment. Proc Natl Acad Sci U S A 107 : 16257 16261.[PubMed] [CrossRef]
5. Bradley TR,, Metcalf D . 1966. The growth of mouse bone marrow cells in vitro . Aust J Exp Biol Med Sci 44 : 287 299.[PubMed] [CrossRef]
6. Ichikawa Y,, Pluznik DH,, Sachs L . 1966. In vitro control of the development of macrophage and granulocyte colonies. Proc Natl Acad Sci U S A 56 : 488 495.[PubMed] [CrossRef]
7. Metcalf D,, Nicola NA . 1995. The Hemopoietic Colony-Stimulating Factors: From Biology to Clinical Applications. Cambridge University Press, Cambridge, United Kingdom. [CrossRef]
8. Nicola NA,, Peterson L,, Hilton DJ,, Metcalf D . 1988. Cellular processing of murine colony-stimulating factor (Multi-CSF, GM-CSF, G-CSF) receptors by normal hemopoietic cells and cell lines. Growth Factors 1 : 41 49.[PubMed] [CrossRef]
9. Metcalf D,, Willson TA,, Hilton DJ,, Di Rago L,, Mifsud S . 1995. Production of hematopoietic regulatory factors in cultures of adult and fetal mouse organs: measurement by specific bioassays. Leukemia 9 : 1556 1564.[PubMed]
10. Stein J,, Borzillo GV,, Rettenmier CW . 1990. Direct stimulation of cells expressing receptors for macrophage colony-stimulating factor (CSF-1) by a plasma membrane-bound precursor of human CSF-1. Blood 76 : 1308 1314.[PubMed]
11. Miyake T,, Kung CK,, Goldwasser E . 1977. Purification of human erythropoietin. J Biol Chem 252 : 5558 5564.[PubMed]
12. Sanderson CJ . 1992. Interleukin-5, eosinophils, and disease. Blood 79 : 3101 3109.[PubMed]
13. Tanaka T,, Kishimoto T . 2014. The biology and medical implications of interleukin-6. Cancer Immunol Res 2 : 288 294.[PubMed] [CrossRef]
14. Zsebo KM,, Wypych J,, McNiece IK,, Lu HS,, Smith KA,, Karkare SB,, Sachdev RK,, Yuschenkoff VN,, Birkett NC,, Williams LR,, Satyagal VN,, Tung W,, Bosselman RA,, Mendiaz EA,, Langley KE . 1990. Identification, purification, and biological characterization of hematopoietic stem cell factor from buffalo rat liver-conditioned medium. Cell 63 : 195 201.[CrossRef]
15. de Sauvage FJ,, Hass PE,, Spencer SD,, Malloy BE,, Gurney AL,, Spencer SA,, Darbonne WC,, Henzel WJ,, Wong SC,, Kuang WJ,, Oles KJ,, Hultgren B,, Solberg LA,, Goeddel DV,, Eaton DL . 1994. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature 369 : 533 538.[PubMed] [CrossRef]
16. Alexander WS,, Roberts AW,, Nicola NA,, Li R,, Metcalf D . 1996. Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl. Blood 87 : 2162 2170.[PubMed]
17. Lieschke GJ,, Grail D,, Hodgson G,, Metcalf D,, Stanley E,, Cheers C,, Fowler KJ,, Basu S,, Zhan YF,, Dunn AR . 1994. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 84 : 1737 1746.[PubMed]
18. Wiktor-Jedrzejczak W,, Ratajczak MZ,, Ptasznik A,, Sell KW,, Ahmed-Ansari A,, Ostertag W . 1992. CSF-1 deficiency in the op/op mouse has differential effects on macrophage populations and differentiation stages. Exp Hematol 20 : 1004 1010.[PubMed]
19. Kopf M,, Brombacher F,, Hodgkin PD,, Ramsay AJ,, Milbourne EA,, Dai WJ,, Ovington KS,, Behm CA,, Köhler G,, Young IG,, Matthaei KI . 1996. IL-5-deficient mice have a developmental defect in CD5 + B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses. Immunity 4 : 15 24.[PubMed] [CrossRef]
20. Qian H,, Buza-Vidas N,, Hyland CD,, Jensen CT,, Antonchuk J,, Månsson R,, Thoren LA,, Ekblom M,, Alexander WS,, Jacobsen SE . 2007. Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. Cell Stem Cell 1 : 671 684.[PubMed] [CrossRef]
21. Metcalf D,, Nicola NA . 1992. The clonal proliferation of normal mouse hematopoietic cells: enhancement and suppression by colony-stimulating factor combinations. Blood 79 : 2861 2866.[PubMed]
22. Metcalf D,, Di Rago L,, Mifsud S . 2002. Synergistic and inhibitory interactions in the in vitro control of murine megakaryocyte colony formation. Stem Cells 20 : 552 560.[PubMed] [CrossRef]
23. Cynshi O,, Satoh K,, Shimonaka Y,, Hattori K,, Nomura H,, Imai N,, Hirashima K . 1991. Reduced response to granulocyte colony-stimulating factor in W/W v and Sl/Sl d mice. Leukemia 5 : 75 77.[PubMed]
24. Ryan PJ,, Willson T,, Alexander WS,, Di Rago L,, Mifsud S,, Metcalf D . 2001. The multi-organ origin of interleukin-5 in the mouse. Leukemia 15 : 1248 1255.[PubMed] [CrossRef]
25. Williams GT,, Smith CA,, Spooncer E,, Dexter TM,, Taylor DR . 1990. Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis. Nature 343 : 76 79.[PubMed] [CrossRef]
26. Vaux DL,, Cory S,, Adams JM . 1988. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335 : 440 442.[PubMed] [CrossRef]
27. Graf T,, Enver T . 2009. Forcing cells to change lineages. Nature 462 : 587 594.[PubMed] [CrossRef]
28. Riddell J,, Gazit R,, Garrison BS,, Guo G,, Saadatpour A,, Mandal PK,, Ebina W,, Volchkov P,, Yuan GC,, Orkin SH,, Rossi DJ . 2014. Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell 157 : 549 564.[PubMed] [CrossRef]
29. Rieger MA,, Hoppe PS,, Smejkal BM,, Eitelhuber AC,, Schroeder T . 2009. Hematopoietic cytokines can instruct lineage choice. Science 325 : 217 218.[PubMed] [CrossRef]
30. Mossadegh-Keller N,, Sarrazin S,, Kandalla PK,, Espinosa L,, Stanley ER,, Nutt SL,, Moore J,, Sieweke MH . 2013. M-CSF instructs myeloid lineage fate in single haematopoietic stem cells. Nature 497 : 239 243.[PubMed] [CrossRef]
31. Fairbairn LJ,, Cowling GJ,, Reipert BM,, Dexter TM . 1993. Suppression of apoptosis allows differentiation and development of a multipotent hemopoietic cell line in the absence of added growth factors. Cell 74 : 823 832.[PubMed] [CrossRef]
32. Dong F,, van Buitenen C,, Pouwels K,, Hoefsloot LH,, Löwenberg B,, Touw IP . 1993. Distinct cytoplasmic regions of the human granulocyte colony-stimulating factor receptor involved in induction of proliferation and maturation. Mol Cell Biol 13 : 7774 7781.[PubMed] [CrossRef]
33. Dührsen U,, Villeval JL,, Boyd J,, Kannourakis G,, Morstyn G,, Metcalf D . 1988. Effects of recombinant human granulocyte colony-stimulating factor on hematopoietic progenitor cells in cancer patients. Blood 72 : 2074 2081.[PubMed]
34. Socinski MA,, Cannistra SA,, Elias A,, Antman KH,, Schnipper L,, Griffin JD . 1988. Granulocyte-macrophage colony stimulating factor expands the circulating haemopoietic progenitor cell compartment in man. Lancet 1 : 1194 1198.[PubMed] [CrossRef]
35. Papayannopoulou T,, Priestley GV,, Bonig H,, Nakamoto B . 2003. The role of G-protein signaling in hematopoietic stem/progenitor cell mobilization. Blood 101 : 4739 4747.[PubMed] [CrossRef]
36. Krebs DL,, Hilton DJ . 2001. SOCS proteins: negative regulators of cytokine signaling. Stem Cells 19 : 378 387.[PubMed] [CrossRef]
37. Croker BA,, Metcalf D,, Robb L,, Wei W,, Mifsud S,, DiRago L,, Cluse LA,, Sutherland KD,, Hartley L,, Williams E,, Zhang JG,, Hilton DJ,, Nicola NA,, Alexander WS,, Roberts AW . 2004. SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis. Immunity 20 : 153 165.[CrossRef]
38. Phrommintikul A,, Haas SJ,, Elsik M,, Krum H . 2007. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet 369 : 381 388.[PubMed] [CrossRef]
39. de Sauvage FJ,, Carver-Moore K,, Luoh SM,, Ryan A,, Dowd M,, Eaton DL,, Moore MW . 1996. Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. J Exp Med 183 : 651 656.[PubMed] [CrossRef]
40. Ng AP,, Kauppi M,, Metcalf D,, Hyland CD,, Josefsson EC,, Lebois M,, Zhang JG,, Baldwin TM,, Di Rago L,, Hilton DJ,, Alexander WS . 2014. Mpl expression on megakaryocytes and platelets is dispensable for thrombopoiesis but essential to prevent myeloproliferation. Proc Natl Acad Sci U S A 111 : 5884 5889.[PubMed] [CrossRef]
41. Nicola NA, . 1991. Structural and functional characteristics of receptors for colony-stimulating factors (CSFs), p 101 120. In Quesenberry PJ,, Asano S,, Saito K (ed), Hemopoietic Growth Factors. Excerpta Medica, Amsterdam, The Netherlands.
42. Nicholson SE,, Novak U,, Ziegler SF,, Layton JE . 1995. Distinct regions of the granulocyte colony-stimulating factor receptor are required for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44 MAPK . Blood 86 : 3698 3704.[PubMed]
43. Inaba K,, Inaba M,, Romani N,, Aya H,, Deguchi M,, Ikehara S,, Muramatsu S,, Steinman RM . 1992. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med 176 : 1693 1702.[PubMed] [CrossRef]
44. Athanassakis I,, Bleackley RC,, Paetkau V,, Guilbert L,, Barr PJ,, Wegmann TG . 1987. The immunostimulatory effect of T cells and T cell lymphokines on murine fetally derived placental cells. J Immunol 138 : 37 44.[PubMed]
45. Schweizerhof M,, Stösser S,, Kurejova M,, Njoo C,, Gangadharan V,, Agarwal N,, Schmelz M,, Bali KK,, Michalski CW,, Brugger S,, Dickenson A,, Simone DA,, Kuner R . 2009. Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. Nat Med 15 : 802 807.[PubMed] [CrossRef]
46. Hilton DJ,, Gough NM . 1991. Leukemia inhibitory factor: a biological perspective. J Cell Biochem 46 : 21 26.[PubMed] [CrossRef]
47. Moore MA,, Williams N,, Metcalf D . 1973. In vitro colony formation by normal and leukemic human hematopoietic cells: interaction between colony-forming and colony-stimulating cells. J Natl Cancer Inst 50 : 591 602.[PubMed]
48. Lang RA,, Metcalf D,, Gough NM,, Dunn AR,, Gonda TJ . 1985. Expression of a hemopoietic growth factor cDNA in a factor-dependent cell line results in autonomous growth and tumorigenicity. Cell 43 : 531 542.[PubMed] [CrossRef]
49. Perkins A,, Kongsuwan K,, Visvader J,, Adams JM,, Cory S . 1990. Homeobox gene expression plus autocrine growth factor production elicits myeloid leukemia. Proc Natl Acad Sci U S A 87 : 8398 8402.[PubMed] [CrossRef]
50. Metcalf D . 2010. The colony-stimulating factors and cancer. Nat Rev Cancer 10 : 425 434.[PubMed] [CrossRef]
51. Gonda TJ,, D’Andrea RJ . 1997. Activating mutations in cytokine receptors: implications for receptor function and role in disease. Blood 89 : 355 369.[PubMed]
52. Metcalf D,, Roberts AW,, Willson TA . 1996. The regulation of hematopoiesis in max 41 transgenic mice with sustained excess granulopoiesis. Leukemia 10 : 311 320.[PubMed]


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Table 1

Colony-stimulating activity for mouse bone marrow cells of CSFs and other cytokines

Citation: Metcalf† D. 2017. Growth and Differentiation Factors, p 31-41. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0004-2015

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