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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Haeckel, E. Natürliche Schöpfungsgeschichte (Georg Reimer, 1868)
Pappenheim, A. Ueber entwickelung und ausbildung der erythroblasten. Virchows Arch Pathol Anat 145, 587–643 (1896)
Pappenheim, A. Zwei Fälle akuter grosslymphozytärer Leukämie. Fol Haematol 4, 301–308 (1907)
Jacobson, L. O., Simmons, E. L., Marks, E. K. & Eldredge, J. H. Recovery from radiation injury. Science 113, 510–511 (1951)
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)
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)
Spangrude, G. J., Heimfeld, S. & Weissman, I. L. Purification and characterization of mouse hematopoietic stem cells. Science 241, 58–62 (1988)
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)
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)
Goardon, N. et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 19, 138–152 (2011)
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.
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.
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.
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)
Dykstra, B. et al. Long-term propagation of distinct hematopoietic differentiation programs in vivo. Cell Stem Cell 1, 218–229 (2007)
Benveniste, P. et al. Intermediate-term hematopoietic stem cells with extended but time-limited reconstitution potential. Cell Stem Cell 6, 48–58 (2010)
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)
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)
Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008)
Foudi, A. et al. Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nat. Biotechnol. 27, 84–90 (2009)
Cross, M. A. & Enver, T. The lineage commitment of haemopoietic progenitor cells. Curr. Opin. Genet. Dev. 7, 609–613 (1997)
Chambers, S. M. et al. Hematopoietic fingerprints: an expression database of stem cells and their progeny. Cell Stem Cell 1, 578–591 (2007)
Novershtern, N. et al. Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 144, 296–309 (2011)
Laurenti, E. et al. The transcriptional architecture of early human hematopoiesis identifies multilevel control of lymphoid commitment. Nat. Immunol. 14, 756–763 (2013)
Chen, L. et al. Transcriptional diversity during lineage commitment of human blood progenitors. Science 345, 1251033 (2014)
Bock, C. et al. DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. Mol. Cell 47, 633–647 (2012)
Farlik, M. et al. DNA methylation dynamics of human hematopoietic stem cell differentiation. Cell Stem Cell 19, 808–822 (2016)
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)
Ji, H. et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467, 338–342 (2010)
Corces, M. R. et al. Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution. Nat. Genet. 48, 1193–1203 (2016)
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)
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.
Warr, M. R. et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327 (2013)
Ho, T. T. et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature 543, 205–210 (2017)
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)
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)
Vannini, N. et al. Specification of haematopoietic stem cell fate via modulation of mitochondrial activity. Nat. Commun. 7, 13125 (2016)
Ito, K. et al. Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance. Science 354, 1156–1160 (2016)
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)
Mohrin, M. et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 7, 174–185 (2010)
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)
van Galen, P. et al. The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress. Nature 510, 268–272 (2014)
Mohrin, M. et al. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347, 1374–1377 (2015)
van Galen, P. et al. Reduced lymphoid lineage priming promotes human hematopoietic stem cell expansion. Cell Stem Cell 14, 94–106 (2014)
Beer, P. A. et al. A dominant-negative isoform of IKAROS expands primitive normal human hematopoietic cells. Stem Cell Reports 3, 841–857 (2014)
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)
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)
Kent, D. G. et al. Prospective isolation and molecular characterization of hematopoietic stem cells with durable self-renewal potential. Blood 113, 6342–6350 (2009)
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)
Notta, F. et al. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science 333, 218–221 (2011)
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)
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)
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)
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.
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)
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)
Säwén, P. et al. Mitotic history reveals distinct stem cell populations and their contributions to hematopoiesis. Cell Reports 14, 2809–2818 (2016)
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)
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)
Carrelha, J. et al. Hierarchically related lineage-restricted fates of multipotent hematopoietic stem cells. Nature https://doi.org/10.1038/nature25455 (2017)
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.
Haas, S. et al. Inflammation-induced emergency megakaryopoiesis driven by hematopoietic stem cell-like megakaryocyte progenitors. Cell Stem Cell 17, 422–434 (2015)
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)
Yu, V. W. C. et al. Epigenetic memory underlies cell-autonomous heterogeneous behavior of hematopoietic stem cells. Cell 167, 1310–1322 (2016)
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)
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)
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)
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)
Morita, Y., Ema, H. & Nakauchi, H. Heterogeneity and hierarchy within the most primitive hematopoietic stem cell compartment. J. Exp. Med. 207, 1173–1182 (2010)
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)
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.
Psaila, B. et al. Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways. Genome Biol. 17, 83 (2016)
Miyawaki, K. et al. Identification of unipotent megakaryocyte progenitors in human hematopoiesis. Blood 129, 3332–3343 (2017)
Sanada, C. et al. Adult human megakaryocyte-erythroid progenitors are in the CD34+CD38mid fraction. Blood 128, 923–933 (2016)
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)
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)
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)
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)
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)
Guo, G. et al. Mapping cellular hierarchy by single-cell analysis of the cell surface repertoire. Cell Stem Cell 13, 492–505 (2013)
Pina, C. et al. Inferring rules of lineage commitment in haematopoiesis. Nat. Cell Biol. 14, 287–294 (2012)
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)
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.
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.
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)
Haghverdi, L., Buettner, F. & Theis, F. J. Diffusion maps for high-dimensional single-cell analysis of differentiation data. Bioinformatics 31, 2989–2998 (2015)
Grün, D. et al. De novo prediction of stem cell identity using single-cell transcriptome data. Cell Stem Cell 19, 266–277 (2016)
Setty, M. et al. Wishbone identifies bifurcating developmental trajectories from single-cell data. Nat. Biotechnol. 34, 637–645 (2016)
Olsson, A. et al. Single-cell analysis of mixed-lineage states leading to a binary cell fate choice. Nature 537, 698–702 (2016)
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.
Naik, S. H. et al. Diverse and heritable lineage imprinting of early haematopoietic progenitors. Nature 496, 229–232 (2013)
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)
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)
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)
Lemischka, I. R., Raulet, D. H. & Mulligan, R. C. Developmental potential and dynamic behavior of hematopoietic stem cells. Cell 45, 917–927 (1986)
Sun, J. et al. Clonal dynamics of native haematopoiesis. Nature 514, 322–327 (2014)
Pei, W. et al. Polylox barcoding reveals haematopoietic stem cell fates realized in vivo. Nature 548, 456–460 (2017)
Sawai, C. M. et al. Hematopoietic stem cells are the major source of multilineage hematopoiesis in adult animals. Immunity 45, 597–609 (2016)
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.
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)
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)
Behjati, S. et al. Genome sequencing of normal cells reveals developmental lineages and mutational processes. Nature 513, 422–425 (2014)
Biezuner, T. et al. A generic, cost-effective, and scalable cell lineage analysis platform. Genome Res. 26, 1588–1599 (2016)
Ivanovs, A. et al. Human haematopoietic stem cell development: from the embryo to the dish. Development 144, 2323–2337 (2017)
Copley, M. R. & Eaves, C. J. Developmental changes in hematopoietic stem cell properties. Exp. Mol. Med. 45, e55 (2013)
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)
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)
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.
Geiger, H., de Haan, G. & Florian, M. C. The ageing haematopoietic stem cell compartment. Nat. Rev. Immunol. 13, 376–389 (2013)
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)
Grover, A. et al. Single-cell RNA sequencing reveals molecular and functional platelet bias of aged haematopoietic stem cells. Nat. Commun. 7, 11075 (2016)
Beerman, I. & Rossi, D. J. Epigenetic control of stem cell potential during homeostasis, aging, and disease. Cell Stem Cell 16, 613–625 (2015)
Flach, J. et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 512, 198–202 (2014)
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)
Baryawno, N., Severe, N. & Scadden, D. T. Hematopoiesis: reconciling historic controversies about the niche. Cell Stem Cell 20, 590–592 (2017)
Méndez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008)
Inra, C. N. et al. A perisinusoidal niche for extramedullary haematopoiesis in the spleen. Nature 527, 466–471 (2015)
Lefrançais, E. et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature 544, 105–109 (2017)
Takizawa, H., Boettcher, S. & Manz, M. G. Demand-adapted regulation of early hematopoiesis in infection and inflammation. Blood 119, 2991–3002 (2012)
Matatall, K. A. et al. Chronic infection depletes hematopoietic stem cells through stress-induced terminal differentiation. Cell Reports 17, 2584–2595 (2016)
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)
Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014)
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)
Hérault, A. et al. Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis. Nature 544, 53–58 (2017)
Naldini, L. Gene therapy returns to centre stage. Nature 526, 351–360 (2015)
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)
Steensma, D. P. The beginning of the end of the beginning in cancer genomics. N. Engl. J. Med. 368, 2138–2140 (2013)
Chung, S. S. et al. Hematopoietic stem cell origin of BRAFV600E mutations in hairy cell leukemia. Sci. Transl. Med. 6, 238ra71 (2014)
Horton, S. J. et al. Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors. Nat. Cell Biol. 19, 1093–1104 (2017)
Eppert, K. et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat. Med. 17, 1086–1093 (2011)
Levine, J. H. et al. Data-driven phenotypic dissection of AML reveals progenitor-like cells that correlate with prognosis. Cell 162, 184–197 (2015)
Cosgun, K. N. et al. Kit regulates HSC engraftment across the human-mouse species barrier. Cell Stem Cell 15, 227–238 (2014)
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)
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)
Giustacchini, A. et al. Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nat. Med. 23, 692–702 (2017)
Sugimura, R. et al. Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 545, 432–438 (2017)
Lis, R. et al. Conversion of adult endothelium to immunocompetent haematopoietic stem cells. Nature 545, 439–445 (2017)
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)
Boitano, A. E. et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329, 1345–1348 (2010)
Fares, I. et al. Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science 345, 1509–1512 (2014)
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)
Görgens, A. et al. Revision of the human hematopoietic tree: granulocyte subtypes derive from distinct hematopoietic lineages. Cell Reports 3, 1539–1552 (2013)
Dancey, J. T., Deubelbeiss, K. A., Harker, L. A. & Finch, C. A. Neutrophil kinetics in man. J. Clin. Invest. 58, 705–715 (1976)
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)
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)
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)
Nishikawa, K. et al. Self-association of Gata1 enhances transcriptional activity in vivo in zebra fish embryos. Mol. Cell. Biol. 23, 8295–8305 (2003)
Okuno, Y. et al. Potential autoregulation of transcription factor PU.1 by an upstream regulatory element. Mol. Cell. Biol. 25, 2832–2845 (2005)
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)
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)
Swiers, G., Patient, R. & Loose, M. Genetic regulatory networks programming hematopoietic stem cells and erythroid lineage specification. Dev. Biol. 294, 525–540 (2006)
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.
The authors declare no competing financial interests.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Laurenti, E., Göttgens, B. From haematopoietic stem cells to complex differentiation landscapes. Nature 553, 418–426 (2018). https://doi.org/10.1038/nature25022
Single-cell RNA-seq reveals a concomitant delay in differentiation and cell cycle of aged hematopoietic stem cells
BMC Biology (2021)
Antiplatelet therapy for the prevention of atherosclerosis in chronic kidney disease (ALTAS-CKD) patients: study protocol for a randomized clinical trial
Chromatin accessibility maps provide evidence of multilineage gene priming in hematopoietic stem cells
Epigenetics & Chromatin (2021)
BMC Bioinformatics (2021)
Nature Reviews Methods Primers (2021)