Article

Human haematopoietic stem cell lineage commitment is a continuous process

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Abstract

Blood formation is believed to occur through stepwise progression of haematopoietic stem cells (HSCs) following a tree-like hierarchy of oligo-, bi- and unipotent progenitors. However, this model is based on the analysis of predefined flow-sorted cell populations. Here we integrated flow cytometric, transcriptomic and functional data at single-cell resolution to quantitatively map early differentiation of human HSCs towards lineage commitment. During homeostasis, individual HSCs gradually acquire lineage biases along multiple directions without passing through discrete hierarchically organized progenitor populations. Instead, unilineage-restricted cells emerge directly from a ‘continuum of low-primed undifferentiated haematopoietic stem and progenitor cells’ (CLOUD-HSPCs). Distinct gene expression modules operate in a combinatorial manner to control stemness, early lineage priming and the subsequent progression into all major branches of haematopoiesis. These data reveal a continuous landscape of human steady-state haematopoiesis downstream of HSCs and provide a basis for the understanding of haematopoietic malignancies.

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Acknowledgements

We thank C. Drumm for help with 3D graphics, K. Hexel, S. Schmitt, C. Felbinger and M. Eich from the DKFZ flow cytometry facility for flow cytometry support, the EMBL Genomics Core Facility for sequencing and R. Aiyar, A. Jones, M. Milsom and all members of HI-STEM and the Steinmetz group for helpful discussions on the manuscript as well as T. Schroeder and D. Löffler for initial discussions. This work was supported by the SFB873 funded by the Deutsche Forschungsgemeinschaft (DFG) (to C.L., M.A.G.E. and A.T.), the Dietmar Hopp Foundation (to M.A.G.E. and A.T.) and the US National Institutes of Health (P01 HG000205 to L.M.S.).

Author information

Author notes

    • Lars Velten
    • , Simon F. Haas
    •  & Simon Raffel

    These authors contributed equally to this work.

    • Andreas Trumpp
    • , Marieke A. G. Essers
    •  & Lars M. Steinmetz

    These authors jointly supervised this work.

Affiliations

  1. European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany

    • Lars Velten
    • , Bianca P. Hennig
    • , Wolfgang Huber
    •  & Lars M. Steinmetz
  2. Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany

    • Simon F. Haas
    • , Simon Raffel
    • , Sandra Blaszkiewicz
    • , Christoph Hirche
    • , Andreas Trumpp
    •  & Marieke A. G. Essers
  3. Division of Stem Cells and Cancer, Haematopoietic Stem Cells and Stress Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

    • Simon F. Haas
    • , Sandra Blaszkiewicz
    • , Christoph Hirche
    •  & Marieke A. G. Essers
  4. Division of Stem Cells and Cancer and DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

    • Simon F. Haas
    • , Simon Raffel
    •  & Andreas Trumpp
  5. Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany

    • Simon Raffel
    • , Christoph Lutz
    • , Eike C. Buss
    •  & Anthony D. Ho
  6. Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA

    • Saiful Islam
    •  & Lars M. Steinmetz
  7. Department of Hematology and Oncology, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany

    • Daniel Nowak
    • , Tobias Boch
    •  & Wolf-Karsten Hofmann
  8. German Cancer Consortium (DKTK), 69120 Heidelberg, Germany

    • Andreas Trumpp
  9. Stanford Genome Technology Center, Palo Alto, California 94304, USA

    • Lars M. Steinmetz

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Contributions

S.F.H., S.R., L.V., S.B. and C.H. performed the experiments. L.V. analysed the data, with conceptual input from S.F.H., S.R., L.M.S., M.A.G.E. and A.T., and analytical advice from W.H. S.I. and B.P.H. optimized genomics methods. C.L., E.C.B., D.N., T.B., W.-K.H. and A.D.H. obtained bone marrow aspirates. L.V., S.F.H., S.R., M.A.G.E., L.M.S. and A.T. jointly conceived and designed the study, and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Andreas Trumpp or Marieke A. G. Essers or Lars M. Steinmetz.

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