Letter | Published:

Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells

Nature volume 554, pages 106111 (01 February 2018) | Download Citation


Rare multipotent haematopoietic stem cells (HSCs) in adult bone marrow with extensive self-renewal potential can efficiently replenish all myeloid and lymphoid blood cells1, securing long-term multilineage reconstitution after physiological and clinical challenges such as chemotherapy and haematopoietic transplantations2,3,4. HSC transplantation remains the only curative treatment for many haematological malignancies, but inefficient blood-lineage replenishment remains a major cause of morbidity and mortality5,6. Single-cell transplantation has uncovered considerable heterogeneity among reconstituting HSCs7,8,9,10,11, a finding that is supported by studies of unperturbed haematopoiesis2,3,4,12 and may reflect different propensities for lineage-fate decisions by distinct myeloid-, lymphoid- and platelet-biased HSCs7,8,9,10,13. Other studies suggested that such lineage bias might reflect generation of unipotent or oligopotent self-renewing progenitors within the phenotypic HSC compartment, and implicated uncoupling of the defining HSC properties of self-renewal and multipotency11,14. Here we use highly sensitive tracking of progenitors and mature cells of the megakaryocyte/platelet, erythroid, myeloid and B and T cell lineages, produced from singly transplanted HSCs, to reveal a highly organized, predictable and stable framework for lineage-restricted fates of long-term self-renewing HSCs. Most notably, a distinct class of HSCs adopts a fate towards effective and stable replenishment of a megakaryocyte/platelet-lineage tree but not of other blood cell lineages, despite sustained multipotency. No HSCs contribute exclusively to any other single blood-cell lineage. Single multipotent HSCs can also fully restrict towards simultaneous replenishment of megakaryocyte, erythroid and myeloid lineages without executing their sustained lymphoid lineage potential. Genetic lineage-tracing analysis also provides evidence for an important role of platelet-biased HSCs in unperturbed adult haematopoiesis. These findings uncover a limited repertoire of distinct HSC subsets, defined by a predictable and hierarchical propensity to adopt a fate towards replenishment of a restricted set of blood lineages, before loss of self-renewal and multipotency.

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  1. 1.

    , , & Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273, 242–245 (1996)

  2. 2.

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

  3. 3.

    et al. Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature 518, 542–546 (2015)

  4. 4.

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

  5. 5.

    & Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update. Blood 115, 3861–3868 (2010)

  6. 6.

    & Cellular-based therapies to prevent or reduce thrombocytopenia. Transfusion 51, 72S–81S (2011)

  7. 7.

    , , , & Deterministic regulation of hematopoietic stem cell self-renewal and differentiation. Blood 100, 1302–1309 (2002)

  8. 8.

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

  9. 9.

    , , & Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-β1. Cell Stem Cell 6, 265–278 (2010)

  10. 10.

    et al. Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy. Nature 502, 232–236 (2013)

  11. 11.

    et al. Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells. Cell 154, 1112–1126 (2013)

  12. 12.

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

  13. 13.

    et al. Per2 induction limits lymphoid-biased haematopoietic stem cells and lymphopoiesis in the context of DNA damage and ageing. Nat. Cell Biol. 18, 480–490 (2016)

  14. 14.

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

  15. 15.

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

  16. 16.

    , & SLAM family markers are conserved among hematopoietic stem cells from old and reconstituted mice and markedly increase their purity. Blood 107, 924–930 (2006)

  17. 17.

    , & SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors. Cell Stem Cell 13, 102–116 (2013)

  18. 18.

    et al. Distinct myeloid progenitor-differentiation pathways identified through single-cell RNA sequencing. Nat. Immunol. 17, 666–676 (2016)

  19. 19.

    Microenvironmental niches in the bone marrow required for B-cell development. Nat. Rev. Immunol. 6, 107–116 (2006)

  20. 20.

    , , & Commitment and developmental potential of extrathymic and intrathymic T cell precursors: plenty to choose from. Immunity 26, 678–689 (2007)

  21. 21.

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

  22. 22.

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

  23. 23.

    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)

  24. 24.

    et al. Molecular evidence for hierarchical transcriptional lineage priming in fetal and adult stem cells and multipotent progenitors. Immunity 26, 407–419 (2007)

  25. 25.

    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)

  26. 26.

    et al. Lymphomyeloid contribution of an immune-restricted progenitor emerging prior to definitive hematopoietic stem cells. Cell Stem Cell 13, 535–548 (2013)

  27. 27.

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

  28. 28.

    Hematopoietic stem cells: concepts, definitions, and the new reality. Blood 125, 2605–2613 (2015)

  29. 29.

    & Lymphocyte life-span and memory. Science 265, 1395–1400 (1994)

  30. 30.

    et al. Autologous peripheral blood stem cell transplantation in patients with relapsed lymphoma results in accelerated haematopoietic reconstitution, improved quality of life and cost reduction compared with bone marrow transplantation: the Hovon 22 study. Br. J. Haematol. 114, 319–326 (2001)

  31. 31.

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

  32. 32.

    et al. Initial seeding of the embryonic thymus by immune-restricted lympho-myeloid progenitors. Nat. Immunol. 17, 1424–1435 (2016)

  33. 33.

    et al. Persistent malignant stem cells in del(5q) myelodysplasia in remission. N. Engl. J. Med. 363, 1025–1037 (2010)

  34. 34.

    , , , & EDISON-WMW: Exact dynamic programing solution of the Wilcoxon–Mann–Whitney test. Genomics Proteomics Bioinformatics 14, 55–61 (2016)

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We thank A. J. Mead, D. Atkinson, A. Giustacchini and N. Ashley for expert assistance with the Fluidigm array platform (WIMM Single Cell Core Facility is supported by the Medical Research Council (MRC) MHU (MC_UU_12009), the Oxford Single Cell Biology Consortium (MR/M00919X/1), the WT-ISSF (097813/Z/11/B#) and the WIMM Strategic Alliance awards G0902418 and MC_UU_12025); P. Sopp and S. A. Clark for expert flow cytometry technical support and cell-sorting services (WIMM FACS Core Facility is supported by the MRC HIU, MRC MHU (MC_UU_12009), NIHR Oxford BRC and the John Fell Fund (131/030 and 101/517), the EPA fund (CF182 and CF170) and by WIMM Strategic Alliance awards (G0902418 and MC_UU_12025)); the Biomedical Services at University of Oxford for animal technical support; the EMBL Monterotondo Gene Expression Service and Transgenic Core Facility for generating the Vwf-tdTomato BAC and the corresponding transgenic mouse line; N. Iscove for KitW41/W41 mice; A. Cumano for OP9-DL1 stromal cells; R. Drissen and S. Duarte for discussions and assistance with the preliminary phase of the studies; A. Hillen, B. Wu and T. Bouriez-Jones for technical assistance. This work was supported by Marie Curie Early Stage Researcher Fellowship (J.C.), the MRC UK (G0801073 and MC_UU_12009/5 to S.E.W.J. and G0701761, G0900892 and MC_UU_12009/7 to C.N.), the Swedish Research Council (S.E.W.J.), the Knut och Alice Wallenberg Foundation (WIRM; S.E.W.J.), the Tobias Foundation (S.E.W.J.), StratRegen KI (S.E.W.J.), Bloodwise (project grant 15006 to C.N.) and a BBSRC Project Grant (BB/M024350/1 to C.N.).

Author information

Author notes

    • Hanane Boukarabila
    •  & Alejandra Sanjuan-Pla

    Present address: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229, USA (H.B.); Hematology Research Group, Instituto de Investigación Sanitaria La Fe, Valencia 46026, Spain (A.S.-P.).

    • Claus Nerlov
    •  & Sten Eirik W. Jacobsen

    These authors contributed equally to this work.


  1. Haematopoietic Stem Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK

    • Joana Carrelha
    • , Yiran Meng
    • , Tiago C. Luis
    • , Ruggiero Norfo
    • , Verónica Alcolea
    • , Hanane Boukarabila
    •  & Sten Eirik W. Jacobsen
  2. MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK

    • Joana Carrelha
    • , Yiran Meng
    • , Tiago C. Luis
    • , Ruggiero Norfo
    • , Verónica Alcolea
    • , Hanane Boukarabila
    • , Adriana Gambardella
    • , Amit Grover
    • , Alejandra Sanjuan-Pla
    • , Claus Nerlov
    •  & Sten Eirik W. Jacobsen
  3. Department of Cell and Molecular Biology, Wallenberg Institute for Regenerative Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden

    • Laura M. Kettyle
    • , Kari Högstrand
    • , Allegra M. Lord
    •  & Sten Eirik W. Jacobsen
  4. Karolinska Institutet, Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm SE-141 86, Sweden

    • Laura M. Kettyle
    • , Francesca Grasso
    • , Kari Högstrand
    • , Allegra M. Lord
    • , Petter S. Woll
    •  & Sten Eirik W. Jacobsen
  5. Karolinska University Hospital, Stockholm SE-141 86, Sweden.

    • Francesca Grasso
    • , Petter S. Woll
    •  & Sten Eirik W. Jacobsen


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S.E.W.J. and C.N. conceptualized the research, with input from A.S.-P. and J.C. S.E.W.J., C.N., J.C., Y.M., L.M.K. and P.S.W. designed the experiments and analysed the data. J.C. and Y.M. performed all experiments except fate mapping, with assistance from T.C.L., A. Ga. and A. Gr. (single-cell transplantations), L.M.K., R.N. and V.A. (peripheral blood reconstitution analysis), H.B. (blood and progenitor reconstitution analysis) and F.G. (CD229/CD41 analysis). L.M.K. performed fate-mapping experiments with assistance from K.H. and A.M.L. S.E.W.J., C.N. and J.C. wrote the manuscript, which was subsequently reviewed and approved by all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Claus Nerlov or Sten Eirik W. Jacobsen.

Reviewer Information Nature thanks E. Laurenti, S. Morrison and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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    Supplementary Tables

    This file contains Supplementary Table 1 (Antibodies and viability dyes used in flow cytometry) and Supplementary Table 2 (TaqMan gene expression assays used in Fluidigm analysis of in vitro myeloid and lymphoid cultures).

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