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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1

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

  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).

  3. 3

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

  4. 4

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

  5. 5

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

  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).

  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).

  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).

  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).

  10. 10

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

  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).

  12. 12

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

  13. 13

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

  14. 14

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

  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).

  16. 16

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

  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.

  18. 18

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

  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.

  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).

  21. 21

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

  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).

  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).

  24. 24

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

  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).

  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).

  27. 27

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

  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.

  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).

  30. 30

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

  31. 31

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

  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.

  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).

  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).

  35. 35

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

  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.

  37. 37

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

  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).

  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).

  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).

  41. 41

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

  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).

  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).

  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).

  45. 45

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

  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).

  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).

  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.

  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).

  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).

  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).

  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).

  53. 53

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

  54. 54

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

  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).

  56. 56

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

  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).

  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).

  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).

  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).

  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.

  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.

  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).

  64. 64

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

  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).

  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).

  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).

  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).

  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).

  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.

  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).

  72. 72

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

  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).

  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).

  75. 75

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

  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).

  77. 77

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

  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).

  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).

  80. 80

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

  81. 81

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

  82. 82

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  90. 90

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

  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).

  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).

  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).

  94. 94

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

  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).

  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).

  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).

  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).

  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).

Download references


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.

Author information

Ethics declarations

Competing interests

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

Additional information

Correspondence should be addressed to the author (

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.