Perspective | Published:

Haematopoiesis in the era of advanced single-cell technologies

Nature Cell Biologyvolume 21pages28 (2019) | Download Citation

Abstract

The molecular and functional characterization of single cells at scale has emerged as a key driver to unravel tissue biology. Thus, it is important to understand the strengths and limitations of transcriptomic approaches, molecular barcoding and functional assays used to study cellular properties at the single-cell level. Here, we review recent relevant work from the haematopoietic system and discuss how to interpret and integrate data obtained with different technologies.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

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

References

  1. 1.

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

  2. 2.

    Laurenti, E. & Gottgens, B. From haematopoietic stem cells to complex differentiation landscapes. Nature 553, 418–426 (2018).

  3. 3.

    McCulloch, E. A. & Till, J. E. The radiation sensitivity of normal mouse bone marrow cells, determined by quantitative marrow transplantation into irradiated mice. Radiat. Res. 13, 115–125 (1960).

  4. 4.

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

  5. 5.

    Osawa, M., Hanada, K., Hamada, H. & Nakauchi, H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273, 242–245 (1996).

  6. 6.

    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).

  7. 7.

    Metcalf, D. Hematopoietic cytokines. Blood 111, 485–491 (2008).

  8. 8.

    Akashi, K., Traver, D., Miyamoto, T. & Weissman, I. L. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000).

  9. 9.

    Kondo, M., Weissman, I. L. & Akashi, K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661–672 (1997).

  10. 10.

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

  11. 11.

    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).

  12. 12.

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

  13. 13.

    Rodriguez-Fraticelli, A. E. et al. Clonal analysis of lineage fate in native haematopoiesis. Nature 553, 212–216 (2018).

  14. 14.

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

  15. 15.

    Yu, V. W. et al. Epigenetic memory underlies cell-autonomous heterogeneous behavior of hematopoietic stem cells. Cell 168, 944–945 (2017).

  16. 16.

    Jones, R. J. & Armstrong, S. A. Cancer stem cells in hematopoietic malignancies. Biol. Blood Marrow Transplant. 14, 12–16 (2008).

  17. 17.

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

  18. 18.

    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).

  19. 19.

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

  20. 20.

    Arinobu, Y. et al. Reciprocal activation of GATA-1 and PU.1 marks initial specification of hematopoietic stem cells into myeloerythroid and myelolymphoid lineages. Cell Stem Cell 1, 416–427 (2007).

  21. 21.

    Miyawaki, K. et al. CD41 marks the initial myelo-erythroid lineage specification in adult mouse hematopoiesis: redefinition of murine common myeloid progenitor. Stem Cells 33, 976–987 (2015).

  22. 22.

    Yanez, A. et al. Granulocyte-monocyte progenitors and monocyte-dendritic cell progenitors independently produce functionally distinct monocytes. Immunity 47, 890–902.e4 (2017).

  23. 23.

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

  24. 24.

    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.e10 (2016).

  25. 25.

    Carrelha, J. et al. Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells. Nature 554, 106–111 (2018).

  26. 26.

    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).

  27. 27.

    Muller-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).

  28. 28.

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

  29. 29.

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

  30. 30.

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

  31. 31.

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

  32. 32.

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

  33. 33.

    Copeland, N. G. & Jenkins, N. A. Harnessing transposons for cancer gene discovery. Nat. Rev. Cancer 10, 696–706 (2010).

  34. 34.

    Kretzschmar, K. & Watt, F. M. Lineage tracing. Cell 148, 33–45 (2012).

  35. 35.

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

  36. 36.

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

  37. 37.

    Perie, L., Duffy, K. R., Kok, L., de Boer, R. J. & Schumacher, T. N. The branching point in erythro-myeloid differentiation. Cell 163, 1655–1662 (2015).

  38. 38.

    Manz, M. G., Miyamoto, T., Akashi, K. & Weissman, I. L. Prospective isolation of human clonogenic common myeloid progenitors. Proc. Natl Acad. Sci. USA 99, 11872–11877 (2002).

  39. 39.

    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).

  40. 40.

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

  41. 41.

    Notta, F. et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science 351, aab2116 (2016).

  42. 42.

    Karamitros, D. et al. Single-cell analysis reveals the continuum of human lympho-myeloid progenitor cells. Nat. Immunol. 19, 85–97 (2018).

  43. 43.

    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).

  44. 44.

    Paul, F. et al. Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 164, 325 (2016).

  45. 45.

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

  46. 46.

    Nestorowa, S. et al. A single-cell resolution map of mouse hematopoietic stem and progenitor cell differentiation. Blood 128, e20–e31 (2016).

  47. 47.

    Velten, L. et al. Human haematopoietic stem cell lineage commitment is a continuous process. Nat. Cell Biol. 19, 271–281 (2017).

  48. 48.

    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).

  49. 49.

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

  50. 50.

    Warren, L. A. et al. Transcriptional instability is not a universal attribute of aging. Aging Cell 6, 775–782 (2007).

  51. 51.

    Kowalczyk, M. S. et al. Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells. Genome Res. 25, 1860–1872 (2015).

  52. 52.

    Hu, M. et al. Multilineage gene expression precedes commitment in the hemopoietic system. Genes Dev. 11, 774–785 (1997).

  53. 53.

    Raj, A. & van Oudenaarden, A. Nature, nurture, or chance: stochastic gene expression and its consequences. Cell 135, 216–226 (2008).

  54. 54.

    Teschendorff, A. E. & Enver, T. Single-cell entropy for accurate estimation of differentiation potency from a cell’s transcriptome. Nat. Commun. 8, 15599 (2017).

  55. 55.

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

  56. 56.

    Buenrostro, J. D. et al. Integrated single-cell analysis maps the continuous regulatory landscape of human hematopoietic differentiation. Cell 173, 1535–1548.e16 (2018).

Download references

Acknowledgements

We thank S. Orkin and S. Morrison for critical reading of the manuscript and P. Woll for figure preparation. Research in the Jacobsen and Nerlov laboratories is supported by Bloodwise, MRC, BBSRC, the Swedish Research Council, the Knut and Alice Wallenberg Foundation and the Tobias Foundation.

Author information

Affiliations

  1. MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK

    • Sten Eirik W. Jacobsen
    •  & Claus Nerlov
  2. Haematopoietic Stem Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK

    • Sten Eirik W. Jacobsen
  3. Department of Cell and Molecular Biology, Wallenberg Institute for Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden

    • Sten Eirik W. Jacobsen
  4. Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden

    • Sten Eirik W. Jacobsen
  5. Karolinska University Hospital, Stockholm, Sweden

    • Sten Eirik W. Jacobsen

Authors

  1. Search for Sten Eirik W. Jacobsen in:

  2. Search for Claus Nerlov in:

Contributions

S.E.W.J. and C.N. contributed equally to the writing and editing of the manuscript as well as to figure preparation.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Sten Eirik W. Jacobsen or Claus Nerlov.

About this article

Publication history

Received

Accepted

Published

Issue Date

DOI

https://doi.org/10.1038/s41556-018-0227-8

Further reading

  • The bone marrow microenvironment at single-cell resolution

    • Anastasia N. Tikhonova
    • , Igor Dolgalev
    • , Hai Hu
    • , Kishor K. Sivaraj
    • , Edlira Hoxha
    • , Álvaro Cuesta-Domínguez
    • , Sandra Pinho
    • , Ilseyar Akhmetzyanova
    • , Jie Gao
    • , Matthew Witkowski
    • , Maria Guillamot
    • , Michael C. Gutkin
    • , Yutong Zhang
    • , Christian Marier
    • , Catherine Diefenbach
    • , Stavroula Kousteni
    • , Adriana Heguy
    • , Hua Zhong
    • , David R. Fooksman
    • , Jason M. Butler
    • , Aris Economides
    • , Paul S. Frenette
    • , Ralf H. Adams
    • , Rahul Satija
    • , Aristotelis Tsirigos
    •  & Iannis Aifantis

    Nature (2019)