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From haematopoietic stem cells to complex differentiation landscapes

Abstract

The development of mature blood cells from haematopoietic stem cells has long served as a model for stem-cell research, with the haematopoietic differentiation tree being widely used as a model for the maintenance of hierarchically organized tissues. Recent results and new technologies have challenged the demarcations between stem and progenitor cell populations, the timing of cell-fate choices and the contribution of stem and multipotent progenitor cells to the maintenance of steady-state blood production. These evolving views of haematopoiesis have broad implications for our understanding of the functions of adult stem cells, as well as the development of new therapies for malignant and non-malignant haematopoietic diseases.

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Figure 1: Timeline of hierarchical models of haematopoiesis.
Figure 2: Trajectory-based visualizations of the haematopoietic hierarchy.
Figure 3: The composition of the HSPC compartment changes in space and time.

References

  1. 1

    Haeckel, E. Natürliche Schöpfungsgeschichte (Georg Reimer, 1868)

  2. 2

    Pappenheim, A. Ueber entwickelung und ausbildung der erythroblasten. Virchows Arch Pathol Anat 145, 587–643 (1896)

    Google Scholar 

  3. 3

    Pappenheim, A. Zwei Fälle akuter grosslymphozytärer Leukämie. Fol Haematol 4, 301–308 (1907)

    Google Scholar 

  4. 4

    Jacobson, L. O., Simmons, E. L., Marks, E. K. & Eldredge, J. H. Recovery from radiation injury. Science 113, 510–511 (1951)

    ADS  CAS  PubMed  Google Scholar 

  5. 5

    Till, J. E. & McCulloch, E. A. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat. Res. 14, 213–222 (1961)

    ADS  CAS  PubMed  Google Scholar 

  6. 6

    Becker, A. J., McCulloch, E. A. & Till, J. E. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 197, 452–454 (1963)

    ADS  CAS  PubMed  Google Scholar 

  7. 7

    Spangrude, G. J., Heimfeld, S. & Weissman, I. L. Purification and characterization of mouse hematopoietic stem cells. Science 241, 58–62 (1988)

    ADS  CAS  Google Scholar 

  8. 8

    Doulatov, S. et al. Revised map of the human progenitor hierarchy shows the origin of macrophages and dendritic cells in early lymphoid development. Nat. Immunol. 11, 585–593 (2010)

    CAS  PubMed  Google Scholar 

  9. 9

    Adolfsson, J. et al. Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment. Cell 121, 295–306 (2005)

    CAS  PubMed  Google Scholar 

  10. 10

    Goardon, N. et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 19, 138–152 (2011)

    CAS  PubMed  Google Scholar 

  11. 11

    Sanjuan-Pla, A. et al. Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy. Nature 502, 232–236 (2013). This study was one of the first to provide evidence of an HSC differentiation bias along the megakaryocyte–platelet lineage.

    ADS  CAS  PubMed  Google Scholar 

  12. 12

    Yamamoto, R. et al. Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells. Cell 154, 1112–1126 (2013). This is a comprehensive single-cell transplantation study that demonstrates that single cells can repopulate long-term after transplantation without contributing to all blood lineages.

    CAS  PubMed  Google Scholar 

  13. 13

    Pietras, E. M. et al. Functionally distinct subsets of lineage-biased multipotent progenitors control blood production in normal and regenerative conditions. Cell Stem Cell 17, 35–46 (2015). This study provides evidence of lineage biases in MPP populations.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Cabezas-Wallscheid, N. et al. Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis. Cell Stem Cell 15, 507–522 (2014)

    CAS  PubMed  Google Scholar 

  15. 15

    Dykstra, B. et al. Long-term propagation of distinct hematopoietic differentiation programs in vivo. Cell Stem Cell 1, 218–229 (2007)

    CAS  PubMed  Google Scholar 

  16. 16

    Benveniste, P. et al. Intermediate-term hematopoietic stem cells with extended but time-limited reconstitution potential. Cell Stem Cell 6, 48–58 (2010)

    CAS  PubMed  Google Scholar 

  17. 17

    Kiel, M. J. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005)

    CAS  Article  Google Scholar 

  18. 18

    Müller-Sieburg, C. E., Cho, R. H., Thoman, M., Adkins, B. & Sieburg, H. B. Deterministic regulation of hematopoietic stem cell self-renewal and differentiation. Blood 100, 1302–1309 (2002)

    PubMed  Google Scholar 

  19. 19

    Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008)

    CAS  PubMed  Google Scholar 

  20. 20

    Foudi, A. et al. Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nat. Biotechnol. 27, 84–90 (2009)

    CAS  PubMed  Google Scholar 

  21. 21

    Cross, M. A. & Enver, T. The lineage commitment of haemopoietic progenitor cells. Curr. Opin. Genet. Dev. 7, 609–613 (1997)

    CAS  PubMed  Google Scholar 

  22. 22

    Chambers, S. M. et al. Hematopoietic fingerprints: an expression database of stem cells and their progeny. Cell Stem Cell 1, 578–591 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Novershtern, N. et al. Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 144, 296–309 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Laurenti, E. et al. The transcriptional architecture of early human hematopoiesis identifies multilevel control of lymphoid commitment. Nat. Immunol. 14, 756–763 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Chen, L. et al. Transcriptional diversity during lineage commitment of human blood progenitors. Science 345, 1251033 (2014)

    PubMed  PubMed Central  Google Scholar 

  26. 26

    Bock, C. et al. DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. Mol. Cell 47, 633–647 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Farlik, M. et al. DNA methylation dynamics of human hematopoietic stem cell differentiation. Cell Stem Cell 19, 808–822 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Bocker, M. T. et al. Genome-wide promoter DNA methylation dynamics of human hematopoietic progenitor cells during differentiation and aging. Blood 117, e182–e189 (2011)

    CAS  PubMed  Google Scholar 

  29. 29

    Ji, H. et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467, 338–342 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Corces, M. R. et al. Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution. Nat. Genet. 48, 1193–1203 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Cheshier, S. H., Morrison, S. J., Liao, X. & Weissman, I. L. In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc. Natl Acad. Sci. USA 96, 3120–3125 (1999)

    ADS  CAS  PubMed  Google Scholar 

  32. 32

    Cabezas-Wallscheid, N. et al. Vitamin A-retinoic acid signaling regulates hematopoietic stem cell dormancy. Cell 169, 807–823 (2017). This is a comprehensive study that describes the molecular circuitry that maintains dormant HSCs.

    CAS  PubMed  Google Scholar 

  33. 33

    Warr, M. R. et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327 (2013)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Ho, T. T. et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature 543, 205–210 (2017)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Simsek, T. et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7, 380–390 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Takubo, K. et al. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 12, 49–61 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Vannini, N. et al. Specification of haematopoietic stem cell fate via modulation of mitochondrial activity. Nat. Commun. 7, 13125 (2016)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Ito, K. et al. Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance. Science 354, 1156–1160 (2016)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Signer, R. A. J., Magee, J. A., Salic, A. & Morrison, S. J. Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature 509, 49–54 (2014)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Mohrin, M. et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 7, 174–185 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Milyavsky, M . et al. A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independent role for p53 in self-renewal. Cell Stem Cell 7, 186–197 (2010)

    CAS  PubMed  Google Scholar 

  42. 42

    van Galen, P. et al. The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress. Nature 510, 268–272 (2014)

    ADS  CAS  PubMed  Google Scholar 

  43. 43

    Mohrin, M. et al. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347, 1374–1377 (2015)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    van Galen, P. et al. Reduced lymphoid lineage priming promotes human hematopoietic stem cell expansion. Cell Stem Cell 14, 94–106 (2014)

    CAS  PubMed  Google Scholar 

  45. 45

    Beer, P. A. et al. A dominant-negative isoform of IKAROS expands primitive normal human hematopoietic cells. Stem Cell Reports 3, 841–857 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Cai, X. et al. Runx1 deficiency decreases ribosome biogenesis and confers stress resistance to hematopoietic stem and progenitor cells. Cell Stem Cell 17, 165–177 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Oguro, H., Ding, L. & Morrison, S. J. SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors. Cell Stem Cell 13, 102–116 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Kent, D. G. et al. Prospective isolation and molecular characterization of hematopoietic stem cells with durable self-renewal potential. Blood 113, 6342–6350 (2009)

    CAS  PubMed  Google Scholar 

  49. 49

    Majeti, R., Park, C. Y. & Weissman, I. L. Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood. Cell Stem Cell 1, 635–645 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Notta, F. et al. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science 333, 218–221 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Takizawa, H., Regoes, R. R., Boddupalli, C. S., Bonhoeffer, S. & Manz, M. G. Dynamic variation in cycling of hematopoietic stem cells in steady state and inflammation. J. Exp. Med. 208, 273–284 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Qiu, J., Papatsenko, D., Niu, X., Schaniel, C. & Moore, K. Divisional history and hematopoietic stem cell function during homeostasis. Stem Cell Reports 2, 473–490 (2014)

    PubMed  PubMed Central  Google Scholar 

  53. 53

    Bernitz, J. M., Kim, H. S., MacArthur, B., Sieburg, H. & Moore, K. Hematopoietic stem cells count and remember self-renewal divisions. Cell 167, 1296–1309 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Laurenti, E. et al. CDK6 levels regulate quiescence exit in human hematopoietic stem cells. Cell Stem Cell 16, 302–313 (2015). This study demonstrates the molecular mechanism by which distinct HSC subsets maintain differentially distinct quiescence exit kinetics.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Zou, P. et al. p57Kip2 and p27Kip1 cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70. Cell Stem Cell 9, 247–261 (2011)

    CAS  PubMed  Google Scholar 

  56. 56

    Laurenti, E. et al. Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity. Cell Stem Cell 3, 611–624 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Säwén, P. et al. Mitotic history reveals distinct stem cell populations and their contributions to hematopoiesis. Cell Reports 14, 2809–2818 (2016)

    PubMed  PubMed Central  Google Scholar 

  58. 58

    Catlin, S. N., Busque, L., Gale, R. E., Guttorp, P. & Abkowitz, J. L. The replication rate of human hematopoietic stem cells in vivo. Blood 117, 4460–4466 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Muller-Sieburg, C. E., Cho, R. H., Karlsson, L., Huang, J.-F. & Sieburg, H. B. Myeloid-biased hematopoietic stem cells have extensive self-renewal capacity but generate diminished lymphoid progeny with impaired IL-7 responsiveness. Blood 103, 4111–4118 (2004)

    CAS  PubMed  Google Scholar 

  60. 60

    Carrelha, J. et al. Hierarchically related lineage-restricted fates of multipotent hematopoietic stem cells. Nature https://doi.org/10.1038/nature25455 (2017)

    ADS  CAS  PubMed  Google Scholar 

  61. 61

    Rodriguez-Fraticelli, A. E. et al. Clonal analysis of lineage fate in native haematopoiesis. Nature https://doi.org/10.1038/nature25168 (2018). In this study, clonal-tracking analysis of unperturbed haematopoiesis reveals large contribution of single phenotypic HSCs to the production of megakaryocytes and platelets at homeostasis.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Haas, S. et al. Inflammation-induced emergency megakaryopoiesis driven by hematopoietic stem cell-like megakaryocyte progenitors. Cell Stem Cell 17, 422–434 (2015)

    CAS  PubMed  Google Scholar 

  63. 63

    Roch, A., Trachsel, V. & Lutolf, M. P. Brief report: single-cell analysis reveals cell division-independent emergence of megakaryocytes from phenotypic hematopoietic stem cells. Stem Cells 33, 3152–3157 (2015)

    CAS  PubMed  Google Scholar 

  64. 64

    Yu, V. W. C. et al. Epigenetic memory underlies cell-autonomous heterogeneous behavior of hematopoietic stem cells. Cell 167, 1310–1322 (2016)

    CAS  PubMed  Google Scholar 

  65. 65

    Challen, G. A., Boles, N. C., Chambers, S. M. & Goodell, M. A. Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-β1. Cell Stem Cell 6, 265–278 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Luchsinger, L. L., de Almeida, M. J., Corrigan, D. J., Mumau, M. & Snoeck, H.-W. Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential. Nature 529, 528–531 (2016)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Grinenko, T. et al. Clonal expansion capacity defines two consecutive developmental stages of long-term hematopoietic stem cells. J. Exp. Med. 211, 209–215 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Anjos-Afonso, F. et al. CD34 cells at the apex of the human hematopoietic stem cell hierarchy have distinctive cellular and molecular signatures. Cell Stem Cell 13, 161–174 (2013)

    CAS  PubMed  Google Scholar 

  69. 69

    Morita, Y., Ema, H. & Nakauchi, H. Heterogeneity and hierarchy within the most primitive hematopoietic stem cell compartment. J. Exp. Med. 207, 1173–1182 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Kohn, L. A. et al. Lymphoid priming in human bone marrow begins before expression of CD10 with upregulation of L-selectin. Nat. Immunol. 13, 963–971 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Notta, F. et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science 351, aab2116 (2016). This study demonstrates that the structure of the haematopoietic hierarchy and the differentiation journeys downstream of HSCs change over a human lifetime.

    ADS  PubMed  Google Scholar 

  72. 72

    Psaila, B. et al. Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways. Genome Biol. 17, 83 (2016)

    PubMed  PubMed Central  Google Scholar 

  73. 73

    Miyawaki, K. et al. Identification of unipotent megakaryocyte progenitors in human hematopoiesis. Blood 129, 3332–3343 (2017)

    CAS  PubMed  Google Scholar 

  74. 74

    Sanada, C. et al. Adult human megakaryocyte-erythroid progenitors are in the CD34+CD38mid fraction. Blood 128, 923–933 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Pronk, C. J. H. et al. Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. Cell Stem Cell 1, 428–442 (2007)

    CAS  PubMed  Google Scholar 

  76. 76

    Lee, J. et al. Lineage specification of human dendritic cells is marked by IRF8 expression in hematopoietic stem cells and multipotent progenitors. Nat. Immunol. 18, 877–888 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Brady, G., Barbara, M. & Iscove, N. Representative in vitro cDNA amplification from individual hemopoietic cells and colonies. Methods Mol. Cell. Biol. 2, 17–25 (1990)

    CAS  Google Scholar 

  78. 78

    Warren, L., Bryder, D., Weissman, I. L. & Quake, S. R. Transcription factor profiling in individual hematopoietic progenitors by digital RT-PCR. Proc. Natl Acad. Sci. USA 103, 17807–17812 (2006)

    ADS  CAS  PubMed  Google Scholar 

  79. 79

    Moignard, V. et al. Characterization of transcriptional networks in blood stem and progenitor cells using high-throughput single-cell gene expression analysis. Nat. Cell Biol. 15, 363–372 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Guo, G. et al. Mapping cellular hierarchy by single-cell analysis of the cell surface repertoire. Cell Stem Cell 13, 492–505 (2013)

    CAS  PubMed  Google Scholar 

  81. 81

    Pina, C. et al. Inferring rules of lineage commitment in haematopoiesis. Nat. Cell Biol. 14, 287–294 (2012)

    CAS  PubMed  Google Scholar 

  82. 82

    Wilson, N. K. et al. Combined single-cell functional and gene expression analysis resolves heterogeneity within stem cell populations. Cell Stem Cell 16, 712–724 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Paul, F. et al. Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 163, 1663–1677 (2015). This is a comprehensive single-cell RNA-seq study of the myelo-erythroid progenitor compartment.

    CAS  PubMed  Google Scholar 

  84. 84

    Nestorowa, S. et al. A single cell resolution map of mouse haematopoietic stem and progenitor cell differentiation. Blood 128, e20–e31 (2016). This study provides the first description of the whole haematopoietic hierarchy by single-cell RNA-seq.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Trapnell, C. et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat. Biotechnol. 32, 381–386 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Haghverdi, L., Buettner, F. & Theis, F. J. Diffusion maps for high-dimensional single-cell analysis of differentiation data. Bioinformatics 31, 2989–2998 (2015)

    CAS  PubMed  Google Scholar 

  87. 87

    Grün, D. et al. De novo prediction of stem cell identity using single-cell transcriptome data. Cell Stem Cell 19, 266–277 (2016)

    PubMed  PubMed Central  Google Scholar 

  88. 88

    Setty, M. et al. Wishbone identifies bifurcating developmental trajectories from single-cell data. Nat. Biotechnol. 34, 637–645 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Olsson, A. et al. Single-cell analysis of mixed-lineage states leading to a binary cell fate choice. Nature 537, 698–702 (2016)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Velten, L. et al. Human haematopoietic stem cell lineage commitment is a continuous process. Nat. Cell Biol. 19, 271–281 (2017). This study couples single-cell RNA-seq and index sorting to delineate differentiation journeys of human HSCs.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Naik, S. H. et al. Diverse and heritable lineage imprinting of early haematopoietic progenitors. Nature 496, 229–232 (2013)

    ADS  CAS  PubMed  Google Scholar 

  92. 92

    Lu, R., Neff, N. F., Quake, S. R. & Weissman, I. L. Tracking single hematopoietic stem cells in vivo using high-throughput sequencing in conjunction with viral genetic barcoding. Nat. Biotechnol. 29, 928–933 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Cheung, A. M. S. et al. Analysis of the clonal growth and differentiation dynamics of primitive barcoded human cord blood cells in NSG mice. Blood 122, 3129–3137 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Dick, J. E., Magli, M. C., Huszar, D., Phillips, R. A. & Bernstein, A. Introduction of a selectable gene into primitive stem cells capable of long-term reconstitution of the hemopoietic system of W/Wv mice. Cell 42, 71–79 (1985)

    CAS  PubMed  Google Scholar 

  95. 95

    Lemischka, I. R., Raulet, D. H. & Mulligan, R. C. Developmental potential and dynamic behavior of hematopoietic stem cells. Cell 45, 917–927 (1986)

    CAS  PubMed  Google Scholar 

  96. 96

    Sun, J. et al. Clonal dynamics of native haematopoiesis. Nature 514, 322–327 (2014)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Pei, W. et al. Polylox barcoding reveals haematopoietic stem cell fates realized in vivo. Nature 548, 456–460 (2017)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Sawai, C. M. et al. Hematopoietic stem cells are the major source of multilineage hematopoiesis in adult animals. Immunity 45, 597–609 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Busch, K. et al. Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature 518, 542–546 (2015). In this study, clonal-tracking analysis is coupled with mathematical modelling to define the flux of stem cells into the different lineage branches under unperturbed and transplantation conditions.

    ADS  CAS  PubMed  Google Scholar 

  100. 100

    Schoedel, K. B. et al. The bulk of the hematopoietic stem cell population is dispensable for murine steady-state and stress hematopoiesis. Blood 128, 2285–2296 (2016)

    CAS  PubMed  Google Scholar 

  101. 101

    Biasco, L. et al. In Vivo tracking of human hematopoiesis reveals patterns of clonal dynamics during early and steady-state reconstitution phases. Cell Stem Cell 19, 107–119 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Behjati, S. et al. Genome sequencing of normal cells reveals developmental lineages and mutational processes. Nature 513, 422–425 (2014)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Biezuner, T. et al. A generic, cost-effective, and scalable cell lineage analysis platform. Genome Res. 26, 1588–1599 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Ivanovs, A. et al. Human haematopoietic stem cell development: from the embryo to the dish. Development 144, 2323–2337 (2017)

    CAS  PubMed  Google Scholar 

  105. 105

    Copley, M. R. & Eaves, C. J. Developmental changes in hematopoietic stem cell properties. Exp. Mol. Med. 45, e55 (2013)

    PubMed  PubMed Central  Google Scholar 

  106. 106

    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)

    ADS  CAS  PubMed  Google Scholar 

  107. 107

    Rufer, N. et al. Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J. Exp. Med. 190, 157–167 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Benz, C . et al. Hematopoietic stem cell subtypes expand differentially during development and display distinct lymphopoietic programs. Cell Stem Cell 10, 273–283 (2012). This study provides evidence that differentiation biases of HSCs change over a lifetime.

    CAS  PubMed  Google Scholar 

  109. 109

    Geiger, H., de Haan, G. & Florian, M. C. The ageing haematopoietic stem cell compartment. Nat. Rev. Immunol. 13, 376–389 (2013)

    CAS  PubMed  Google Scholar 

  110. 110

    Young, K. et al. Progressive alterations in multipotent hematopoietic progenitors underlie lymphoid cell loss in aging. J. Exp. Med. https://doi.org/10.1084/jem.20160168 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Grover, A. et al. Single-cell RNA sequencing reveals molecular and functional platelet bias of aged haematopoietic stem cells. Nat. Commun. 7, 11075 (2016)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Beerman, I. & Rossi, D. J. Epigenetic control of stem cell potential during homeostasis, aging, and disease. Cell Stem Cell 16, 613–625 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Flach, J. et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 512, 198–202 (2014)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Sun, D. et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell 14, 673–688 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Baryawno, N., Severe, N. & Scadden, D. T. Hematopoiesis: reconciling historic controversies about the niche. Cell Stem Cell 20, 590–592 (2017)

    CAS  PubMed  Google Scholar 

  116. 116

    Méndez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008)

    ADS  PubMed  Google Scholar 

  117. 117

    Inra, C. N. et al. A perisinusoidal niche for extramedullary haematopoiesis in the spleen. Nature 527, 466–471 (2015)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Lefrançais, E. et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature 544, 105–109 (2017)

    ADS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Takizawa, H., Boettcher, S. & Manz, M. G. Demand-adapted regulation of early hematopoiesis in infection and inflammation. Blood 119, 2991–3002 (2012)

    CAS  PubMed  Google Scholar 

  120. 120

    Matatall, K. A. et al. Chronic infection depletes hematopoietic stem cells through stress-induced terminal differentiation. Cell Reports 17, 2584–2595 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Hirche, C. et al. Systemic virus infections differentially modulate cell cycle state and functionality of long-term hematopoietic stem cells in vivo. Cell Reports 19, 2345–2356 (2017)

    CAS  PubMed  Google Scholar 

  122. 122

    Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Ambrosi, T. H. et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell 20, 771–784 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Hérault, A. et al. Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis. Nature 544, 53–58 (2017)

    ADS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Naldini, L. Gene therapy returns to centre stage. Nature 526, 351–360 (2015)

    ADS  CAS  PubMed  Google Scholar 

  126. 126

    Cavazzana, M., Ribeil, J.-A., Lagresle-Peyrou, C. & André-Schmutz, I. Gene therapy with hematopoietic stem cells: the diseased bone marrow’s point of view. Stem Cells Dev. 26, 72–76 (2017)

    Google Scholar 

  127. 127

    Steensma, D. P. The beginning of the end of the beginning in cancer genomics. N. Engl. J. Med. 368, 2138–2140 (2013)

    CAS  PubMed  Google Scholar 

  128. 128

    Chung, S. S. et al. Hematopoietic stem cell origin of BRAFV600E mutations in hairy cell leukemia. Sci. Transl. Med. 6, 238ra71 (2014)

    PubMed  PubMed Central  Google Scholar 

  129. 129

    Horton, S. J. et al. Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors. Nat. Cell Biol. 19, 1093–1104 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Eppert, K. et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat. Med. 17, 1086–1093 (2011)

    CAS  PubMed  Google Scholar 

  131. 131

    Levine, J. H. et al. Data-driven phenotypic dissection of AML reveals progenitor-like cells that correlate with prognosis. Cell 162, 184–197 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Cosgun, K. N. et al. Kit regulates HSC engraftment across the human-mouse species barrier. Cell Stem Cell 15, 227–238 (2014)

    CAS  PubMed  Google Scholar 

  133. 133

    Reinisch, A. et al. A humanized bone marrow ossicle xenotransplantation model enables improved engraftment of healthy and leukemic human hematopoietic cells. Nat. Med. 22, 812–821 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Sontakke, P. et al. Modeling BCR-ABL and MLL-AF9 leukemia in a human bone marrow-like scaffold-based xenograft model. Leukemia 30, 2064–2073 (2016)

    CAS  PubMed  Google Scholar 

  135. 135

    Giustacchini, A. et al. Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nat. Med. 23, 692–702 (2017)

    CAS  PubMed  Google Scholar 

  136. 136

    Sugimura, R. et al. Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 545, 432–438 (2017)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Lis, R. et al. Conversion of adult endothelium to immunocompetent haematopoietic stem cells. Nature 545, 439–445 (2017)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Wagner, J. E., Jr et al. Phase I/II trial of stemregenin-1 expanded umbilical cord blood hematopoietic stem cells supports testing as a stand-alone graft. Cell Stem Cell 18, 144–155 (2016)

    CAS  PubMed  Google Scholar 

  139. 139

    Boitano, A. E. et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329, 1345–1348 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Fares, I. et al. Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science 345, 1509–1512 (2014)

    CAS  PubMed  Google Scholar 

  141. 141

    Goodell, M. A., Brose, K., Paradis, G., Conner, A. S. & Mulligan, R. C. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J. Exp. Med. 183, 1797–1806 (1996)

    CAS  PubMed  Google Scholar 

  142. 142

    Görgens, A. et al. Revision of the human hematopoietic tree: granulocyte subtypes derive from distinct hematopoietic lineages. Cell Reports 3, 1539–1552 (2013)

    PubMed  Google Scholar 

  143. 143

    Dancey, J. T., Deubelbeiss, K. A., Harker, L. A. & Finch, C. A. Neutrophil kinetics in man. J. Clin. Invest. 58, 705–715 (1976)

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Hoogenkamp, M. et al. Early chromatin unfolding by RUNX1: a molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program. Blood 114, 299–309 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Hoppe, P. S. et al. Early myeloid lineage choice is not initiated by random PU.1 to GATA1 protein ratios. Nature 535, 299–302 (2016)

    ADS  CAS  PubMed  Google Scholar 

  146. 146

    Rieger, M. A., Hoppe, P. S., Smejkal, B. M., Eitelhuber, A. C. & Schroeder, T. Hematopoietic cytokines can instruct lineage choice. Science 325, 217–218 (2009)

    ADS  CAS  PubMed  Google Scholar 

  147. 147

    Nishikawa, K. et al. Self-association of Gata1 enhances transcriptional activity in vivo in zebra fish embryos. Mol. Cell. Biol. 23, 8295–8305 (2003)

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Okuno, Y. et al. Potential autoregulation of transcription factor PU.1 by an upstream regulatory element. Mol. Cell. Biol. 25, 2832–2845 (2005)

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Pimanda, J. E. et al. Gata2, Fli1, and Scl form a recursively wired gene-regulatory circuit during early hematopoietic development. Proc. Natl Acad. Sci. USA 104, 17692–17697 (2007)

    ADS  CAS  PubMed  Google Scholar 

  150. 150

    Narula, J., Smith, A. M., Gottgens, B. & Igoshin, O. A. Modeling reveals bistability and low-pass filtering in the network module determining blood stem cell fate. PLOS Comput. Biol. 6, e1000771 (2010)

    ADS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Swiers, G., Patient, R. & Loose, M. Genetic regulatory networks programming hematopoietic stem cells and erythroid lineage specification. Dev. Biol. 294, 525–540 (2006)

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank D. Kent for critical reading of the manuscript. E.L. is supported by a Sir Henry Dale fellowship from the Wellcome Trust (WT)/Royal Society. Research in the Laurenti and Gottgens laboratories is supported by the WT, CRUK, Bloodwise, MRC, BBSRC, NIH-NIDDK, and core support grants by the WT and MRC to the Wellcome-MRC Cambridge Stem Cell Institute.

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E.L. and B.G. contributed equally to the writing and editing of the manuscript as well as to figure preparation.

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Correspondence to Elisa Laurenti or Berthold Göttgens.

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Laurenti, E., Göttgens, B. From haematopoietic stem cells to complex differentiation landscapes. Nature 553, 418–426 (2018). https://doi.org/10.1038/nature25022

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