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Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal

Abstract

When stem cells divide, they can generate progeny with the same developmental potential as the original cell, a process referred to as self-renewal. Self-renewal is driven intrinsically by gene expression in a cell-type-specific manner and is modulated through interactions with extrinsic cues from the environment, such as growth factors. However, despite the prevalence of the term self-renewal in the scientific literature, this process has not been defined at the molecular level. Haematopoietic stem cells are an excellent model for the study of self-renewal because they can be isolated prospectively, manipulated relatively easily and assessed by using well-defined assays. Establishing the principles of self-renewal in haematopoietic stem cells will lead to insights into the mechanisms of self-renewal in other tissues.

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Figure 1: Developmental signalling pathways involved in HSC self-renewal.
Figure 2: The Wnt-mediated signalling pathway modifies tissue regeneration.
Figure 3: Pathways that are involved in HSC homeostasis or in tissue regeneration can exhaust HSCs if activated frequently.
Figure 4: Hox genes can increase the self-renewal capacity of haematopoietic cells.

References

  1. 1

    Orkin, S. H. & Zon, L. I. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631–644 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Yilmaz, O. H., Kiel, M. J. & Morrison, S. J. SLAM family markers are conserved among hematopoietic stem cells from old and reconstituted mice and markedly increase their purity. Blood 107, 924–930 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Merkle, F. T. & Alvarez-Buylla, A. Neural stem cells in mammalian development. Curr. Opin. Cell Biol. 18, 704–709 (2006).

    CAS  Google Scholar 

  4. 4

    Fuller, M. T. & Spradling, A. C. Male and female Drosophila germline stem cells: two versions of immortality. Science 316, 402–404 (2007).

    ADS  CAS  Google Scholar 

  5. 5

    Ailles, L. E. & Weissman, I. L. Cancer stem cells in solid tumors. Curr. Opin. Biotechnol. 18, 460–466 (2007).

    CAS  Google Scholar 

  6. 6

    Brummendorf, T. H., Dragowska, W., Zijlmans, J., Thornbury, G. & Lansdorp, P. M. Asymmetric cell divisions sustain long-term hematopoiesis from single-sorted human fetal liver cells. J. Exp. Med. 188, 1117–1124 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Takano, H., Ema, H., Sudo, K. & Nakauchi, H. Asymmetric division and lineage commitment at the level of hematopoietic stem cells: inference from differentiation in daughter cell and granddaughter cell pairs. J. Exp. Med. 199, 295–302 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Beckmann, J., Scheitza, S., Wernet, P., Fischer, J. C. & Giebel, B. Asymmetric cell division within the human hematopoietic stem and progenitor cell compartment: identification of asymmetrically segregating proteins. Blood 109, 5494–5501 (2007).

    CAS  Google Scholar 

  9. 9

    Yamashita, Y. M., Mahowald, A. P., Perlin, J. R. & Fuller, M. T. Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science 315, 518–521 (2007).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Brinster, R. L. Male germline stem cells: from mice to men. Science 316, 404–405 (2007).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Blanpain, C., Lowry, W. E., Geoghegan, A., Polak, L. & Fuchs, E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635–648 (2004).

    CAS  Google Scholar 

  12. 12

    Stingl, J. et al. Purification and unique properties of mammary epithelial stem cells. Nature 439, 993–997 (2006).

    ADS  CAS  Google Scholar 

  13. 13

    Radtke, F. & Clevers, H. Self-renewal and cancer of the gut: two sides of a coin. Science 307, 1904–1909 (2005).

    ADS  CAS  Google Scholar 

  14. 14

    Collins, C. A. & Partridge, T. A. Self-renewal of the adult skeletal muscle satellite cell. Cell Cycle 4, 1338–1341 (2005).

    CAS  Google Scholar 

  15. 15

    Dor, Y., Brown, J., Martinez, O. I. & Melton, D. A. Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429, 41–46 (2004).

    ADS  CAS  PubMed  Google Scholar 

  16. 16

    Pan, G. & Thomson, J. A. Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res. 17, 42–49 (2007).

    CAS  Google Scholar 

  17. 17

    Nakagawa, T., Nabeshima, Y. & Yoshida, S. Functional identification of the actual and potential stem cell compartments in mouse spermatogenesis. Dev. Cell 12, 195–206 (2007).This paper shows that transient amplifying cells in the testes can acquire stem-cell activity and self-renewal.

    CAS  Google Scholar 

  18. 18

    Fuchs, E. Skin stem cells: rising to the surface. J. Cell Biol. 180, 273–284 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Bowie, M. B. et al. Identification of a new intrinsically timed developmental checkpoint that reprograms key hematopoietic stem cell properties. Proc. Natl Acad. Sci. USA 104, 5878–5882 (2007).The paper found that the self-renewal capacity of fetal HSCs differs from that of adult bone-marrow-derived stem cells.

    ADS  CAS  Google Scholar 

  20. 20

    Kim, I., Saunders, T. L. & Morrison, S. J. Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 130, 470–483 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Dzierzak, E. & Speck, N. A. Of lineage and legacy: the development of mammalian hematopoietic stem cells. Nature Immunol. 9, 129–136 (2008).

    CAS  Google Scholar 

  22. 22

    Ober, E. A., Verkade, H., Field, H. A. & Stainier, D. Y. Mesodermal Wnt2b signalling positively regulates liver specification. Nature 442, 688–691 (2006).

    ADS  CAS  Google Scholar 

  23. 23

    McMahon, A. P. & Bradley, A. The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell 62, 1073–1085 (1990).

    CAS  Google Scholar 

  24. 24

    Reya, T. et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423, 409–414 (2003).

    ADS  CAS  Google Scholar 

  25. 25

    Lai, K., Kaspar, B. K., Gage, F. H. & Schaffer, D. V. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nature Neurosci. 6, 21–27 (2003).

    CAS  Google Scholar 

  26. 26

    Kiger, A. A., Jones, D. L., Schulz, C., Rogers, M. B. & Fuller, M. T. Stem cell self-renewal specified by JAK–STAT activation in response to a support cell cue. Science 294, 2542–2545 (2001).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Molofsky, A. V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Koch, U. et al. Simultaneous loss of β- and γ-catenin does not perturb hematopoiesis or lymphopoiesis. Blood 111, 160–164 (2008).This study shows that the WNT-mediated signalling pathway is not required for HSC homeostasis in adulthood, even though WNT proteins are sufficient for the proliferation of HSCs.

    CAS  Google Scholar 

  29. 29

    Zhao, C. et al. Loss of β-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 12, 528–541 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Stoick-Cooper, C. L. et al. Distinct Wnt signaling pathways have opposing roles in appendage regeneration. Development 134, 479–489 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Karlsson, G. et al. Smad4 is critical for self-renewal of hematopoietic stem cells. J. Exp. Med. 204, 467–474 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Whitehead, G. G., Makino, S., Lien, C. L. & Keating, M. T. fgf20 is essential for initiating zebrafish fin regeneration. Science 310, 1957–1960 (2005).This study shows that Fgf20 is a dedicated growth factor for tail-fin regeneration in zebrafish, suggesting that each tissue might have its own set of growth conditions for regeneration.

    ADS  CAS  Google Scholar 

  33. 33

    Bowie, M. B., Kent, D. G., Copley, M. R. & Eaves, C. J. Steel factor responsiveness regulates the high self-renewal phenotype of fetal hematopoietic stem cells. Blood 109, 5043–5048 (2007).

    CAS  Google Scholar 

  34. 34

    Kirstetter, P., Anderson, K., Porse, B. T., Jacobsen, S. E. & Nerlov, C. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nature Immunol. 7, 1048–1056 (2006).

    CAS  Google Scholar 

  35. 35

    Scheller, M. et al. Hematopoietic stem cell and multilineage defects generated by constitutive β-catenin activation. Nature Immunol. 7, 1037–1047 (2006).

    CAS  Google Scholar 

  36. 36

    Bondos, S. Variations on a theme: Hox and Wnt combinatorial regulation during animal development. Sci. STKE 2006, pe38 (2006).References 35 and 36 show that constitutive activation of β-catenin leads to a block in differentiation and indicates that repeated activation of pathways that increase HSC number can lead to stem-cell exhaustion.

    Google Scholar 

  37. 37

    Pilon, N. et al. Cdx4 is a direct target of the canonical Wnt pathway. Dev. Biol. 289, 55–63 (2006).

    CAS  Google Scholar 

  38. 38

    Davidson, A. J. et al. cdx4 mutants fail to specify blood progenitors and can be rescued by multiple hox genes. Nature 425, 300–306 (2003).

    ADS  CAS  Google Scholar 

  39. 39

    Sauvageau, G. et al. Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev. 9, 1753–1765 (1995).

    CAS  Google Scholar 

  40. 40

    Thorsteinsdottir, U. et al. Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion. Blood 99, 121–129 (2002).

    CAS  Google Scholar 

  41. 41

    Magnusson, M. et al. HOXA10 is a critical regulator for hematopoietic stem cells and erythroid/megakaryocyte development. Blood 109, 3687–3696 (2007).

    CAS  Google Scholar 

  42. 42

    Schnabel, C. A., Jacobs, Y. & Cleary, M. L. HoxA9-mediated immortalization of myeloid progenitors requires functional interactions with TALE cofactors Pbx and Meis. Oncogene 19, 608–616 (2000).

    CAS  Google Scholar 

  43. 43

    Magnusson, M., Brun, A. C., Lawrence, H. J. & Karlsson, S. Hoxa9/hoxb3/hoxb4 compound null mice display severe hematopoietic defects. Exp. Hematol. 35, 1421–1428 (2007).

    CAS  Google Scholar 

  44. 44

    Park, I. K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003).

    ADS  CAS  Google Scholar 

  45. 45

    Lessard, J. & Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260 (2003).

    ADS  CAS  Google Scholar 

  46. 46

    Lessard, J. et al. Functional antagonism of the Polycomb-group genes eed and Bmi1 in hemopoietic cell proliferation. Genes Dev. 13, 2691–2703 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Oguro, H. et al. Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice. J. Exp. Med. 203, 2247–2253 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Bruggeman, S. W. et al. Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Genes Dev. 19, 1438–1443 (2005).References 47 and 48 show that the chromatin-associated factor BMI1 controls the cell cycle of stem cells by altering expression of INK4A and ARF.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Datta, S. et al. Bmi-1 cooperates with H-Ras to transform human mammary epithelial cells via dysregulation of multiple growth-regulatory pathways. Cancer Res. 67, 10286–10295 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Liu, S. et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 66, 6063–6071 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Molofsky, A. V., He, S., Bydon, M., Morrison, S. J. & Pardal, R. Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev. 19, 1432–1437 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Tateishi, K. et al. Dysregulated expression of stem cell factor Bmi1 in precancerous lesions of the gastrointestinal tract. Clin. Cancer Res. 12, 6960–6966 (2006).

    CAS  Google Scholar 

  53. 53

    Krivtsov, A. V. et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9. Nature 442, 818–822 (2006).

    ADS  CAS  Google Scholar 

  54. 54

    Ernst, P. et al. Definitive hematopoiesis requires the mixed-lineage leukemia gene. Dev. Cell 6, 437–443 (2004).

    CAS  Google Scholar 

  55. 55

    Tadokoro, Y., Ema, H., Okano, M., Li, E. & Nakauchi, H. De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells. J. Exp. Med. 204, 715–722 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    North, T. E. et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 447, 1007–1011 (2007).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Diamandis, P. et al. Chemical genetics reveals a complex functional ground state of neural stem cells. Nature Chem. Biol. 3, 268–273 (2007).

    CAS  Google Scholar 

  58. 58

    Shiotsugu, J. et al. Multiple points of interaction between retinoic acid and FGF signaling during embryonic axis formation. Development 131, 2653–2567 (2004).

    CAS  Google Scholar 

  59. 59

    Nordstrom, U., Maier, E., Jessell, T. M. & Edlund, T. An early role for WNT signaling in specifying neural patterns of Cdx and Hox gene expression and motor neuron subtype identity. PLoS Biol. 4, e252 (2006).

    PubMed  PubMed Central  Google Scholar 

  60. 60

    Purton, L. E. et al. RARγ is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation. J. Exp. Med. 203, 1283–1293 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Nerlov, C. & Graf, T. PU.1 induces myeloid lineage commitment in multipotent hematopoietic progenitors. Genes Dev. 12, 2403–2412 (1998).This paper reports that the overexpression of transcription factors can lead to an altered cell-fate programme.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Rekhtman, N., Radparvar, F., Evans, T. & Skoultchi, A. I. Direct interaction of hematopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells. Genes Dev. 13, 1398–1411 (1999).This study found that competition between transcription factors can alter cell-fate decisions.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Galloway, J. L., Wingert, R. A., Thisse, C., Thisse, B. & Zon, L. I. Loss of gata1 but not gata2 converts erythropoiesis to myelopoiesis in zebrafish embryos. Dev. Cell 8, 109–116 (2005).

    CAS  Google Scholar 

  64. 64

    Rodrigues, N. P. et al. Haploinsufficiency of GATA-2 perturbs adult hematopoietic stem-cell homeostasis. Blood 106, 477–484 (2005).

    CAS  Google Scholar 

  65. 65

    Zeng, H., Yucel, R., Kosan, C., Klein-Hitpass, L. & Moroy, T. Transcription factor Gfi1 regulates self-renewal and engraftment of hematopoietic stem cells. EMBO J. 23, 4116–4125 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Wilson, A. et al. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 18, 2747–2763 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    CAS  Google Scholar 

  68. 68

    Jankovic, V. et al. Id1 restrains myeloid commitment, maintaining the self-renewal capacity of hematopoietic stem cells. Proc. Natl Acad. Sci. USA 104, 1260–1265 (2007).

    ADS  CAS  Google Scholar 

  69. 69

    Hollnagel, A., Oehlmann, V., Heymer, J., Ruther, U. & Nordheim, A. Id genes are direct targets of bone morphogenetic protein induction in embryonic stem cells. J. Biol. Chem. 274, 19838–19845 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Galan-Caridad, J. M. et al. Zfx controls the self-renewal of embryonic and hematopoietic stem cells. Cell 129, 345–357 (2007).This paper shows that the transcription factor ZFX is required for the self-renewal of several stem-cell populations.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Ramalho-Santos, M., Yoon, S., Matsuzaki, Y., Mulligan, R. C. & Melton, D. A. 'Stemness': transcriptional profiling of embryonic and adult stem cells. Science 298, 597–600 (2002).

    ADS  CAS  Google Scholar 

  72. 72

    Ivanova, N. B. et al. A stem cell molecular signature. Science 298, 601–604 (2002).

    ADS  CAS  Google Scholar 

  73. 73

    Varnum-Finney, B. et al. The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells. Blood 91, 4084–4091 (1998).

    CAS  Google Scholar 

  74. 74

    Stier, S., Cheng, T., Dombkowski, D., Carlesso, N. & Scadden, D. T. Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood 99, 2369–2378 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Zhang, C. C. et al. Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells. Nature Med. 12, 240–245 (2006).

    Google Scholar 

  76. 76

    Petit-Cocault, L., Volle-Challier, C., Fleury, M., Peault, B. & Souyri, M. Dual role of Mpl receptor during the establishment of definitive hematopoiesis. Development 134, 3031–3040 (2007).

    CAS  Google Scholar 

  77. 77

    Janzen, V. et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443, 421–426 (2006).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Yuan, Y., Shen, H., Franklin, D. S., Scadden, D. T. & Cheng, T. In vivo self-renewing divisions of haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18INK4C. Nature Cell Biol. 6, 436–442 (2004).

    CAS  Google Scholar 

  79. 79

    Walkley, C. R., Fero, M. L., Chien, W. M., Purton, L. E. & McArthur, G. A. Negative cell-cycle regulators cooperatively control self-renewal and differentiation of haematopoietic stem cells. Nature Cell Biol. 7, 172–178 (2005).

    CAS  Google Scholar 

  80. 80

    Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287, 1804–1808 (2000).

    ADS  CAS  PubMed  Google Scholar 

  81. 81

    Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006).

    ADS  CAS  Google Scholar 

  82. 82

    Zhang, J. et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 441, 518–522 (2006).

    ADS  CAS  Google Scholar 

  83. 83

    TeKippe, M., Harrison, D. E. & Chen, J. Expansion of hematopoietic stem cell phenotype and activity in Trp53-null mice. Exp. Hematol. 31, 521–527 (2003).

    CAS  Google Scholar 

  84. 84

    Nakamura, T., Largaespada, D. A., Shaughnessy, J. D., Jenkins, N. A. & Copeland, N. G. Cooperative activation of Hoxa and Pbx1-related genes in murine myeloid leukaemias. Nature Genet. 12, 149–153 (1996).

    CAS  Google Scholar 

  85. 85

    Frohling, S., Scholl, C., Bansal, D. & Huntly, B. J. HOX gene regulation in acute myeloid leukemia: CDX marks the spot? Cell Cycle 6, 2241–2245 (2007).

    CAS  Google Scholar 

  86. 86

    Wong, P., Iwasaki, M., Somervaille, T. C., So, C. W. & Cleary, M. L. Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential. Genes Dev. 21, 2762–2774 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Hock, H. et al. Tel/Etv6 is an essential and selective regulator of adult hematopoietic stem cell survival. Genes Dev. 18, 2336–2341 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Passegue, E., Wagner, E. F. & Weissman, I. L. JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 119, 431–443 (2004).

    CAS  Google Scholar 

  89. 89

    Iwasaki, H. et al. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood 106, 1590–1600 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Sandberg, M. L. et al. c-Myb and p300 regulate hematopoietic stem cell proliferation and differentiation. Dev. Cell 8, 153–166 (2005).

    CAS  Google Scholar 

  91. 91

    Rebel, V. I. et al. Distinct roles for CREB-binding protein and p300 in hematopoietic stem cell self-renewal. Proc. Natl Acad. Sci. USA 99, 14789–14794 (2002).

    ADS  CAS  Google Scholar 

  92. 92

    Growney, J. D. et al. Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. Blood 106, 494–504 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Mikkola, H. K. et al. Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene. Nature 421, 547–551 (2003).

    ADS  CAS  Google Scholar 

  94. 94

    Kamminga, L. M. et al. The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood 107, 2170–2179 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Ohta, H. et al. Polycomb group gene rae28 is required for sustaining activity of hematopoietic stem cells. J. Exp. Med. 195, 759–770 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Varnum-Finney, B. et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nature Med. 6, 1278–1281 (2000).

    CAS  Google Scholar 

  97. 97

    Mancini, S. J. et al. Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation. Blood 105, 2340–2342 (2005).

    CAS  PubMed  Google Scholar 

  98. 98

    Congdon, K. L. et al. Activation of Wnt signaling in hematopoietic regeneration. Stem Cells doi:10.1634/stemcells.2007-0768 (in the press).

  99. 99

    Kotake, Y. et al. pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4α tumor suppressor gene. Genes Dev. 21, 49–54 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Bracken, A. P. et al. The Polycomb group proteins bind throughout the INK4A–ARF locus and are disassociated in senescent cells. Genes Dev. 21, 525–530 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I thank G. Sauvageau, S. Cellot and R. Bisaillon, R. Moon and C. Nerlov for providing figures. Work in my laboratory was supported by the Howard Hughes Medical Institute and grants from the National Institutes of Health.

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L.I.Z. is a founder of Fate Therapeutics.

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Correspondence should be addressed to the author (zon@enders.tch.harvard.edu).

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Zon, L. Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal. Nature 453, 306–313 (2008). https://doi.org/10.1038/nature07038

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