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Individual stem cells with highly variable proliferation and self-renewal properties comprise the human hematopoietic stem cell compartment

Nature Immunology volume 7, pages 1225–1233 (2006)Cite this article

Abstract

Hematopoiesis requires tight regulation of the hematopoietic stem cell (HSC) population; however, the dynamics of HSC use at steady state are uncertain. Over 3–7 months, we evaluated the repopulation and self-renewal of more than 600 individual human 'severe combined immunodeficiency mouse–repopulating cells' (SRCs), tracked on the basis of lentiviral integration sites, in serially transplanted immune-deficient mice, as well as of SRC daughter cells that migrated to different marrow locations in a single mouse. Our data demonstrate maintenance by self-renewing SRCs after an initial period of clonal instability, a result inconsistent with the clonal succession model. We found wide variation in proliferation kinetics and self-renewal among SRCs, as well as between SRC daughter cells that repopulated equivalently, suggesting that SRC fate is unpredictable before SRCs enter more rigid 'downstream' developmental programs.

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Figure 1: Study design and multilineage engraftment in primary and secondary recipients of purified human cord blood cells.
Figure 2: Clonal analysis of CD34+CD38lo transplanted serial recipients.
Figure 3: Multilineage engraftment and clonal analysis of CD34+CD38− transplanted serial recipients.
Figure 4: Long-term repopulating kinetics of Lin− cord blood cells.
Figure 5: Clonal dynamics of primary and secondary recipients evaluated over 30 weeks.

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Acknowledgements

We thank P. Scheufler, P. Savage and the obstetrics unit of Trillium Hospital (Mississauga, Ontario) for providing cord blood samples; G. Mallia and S. Zere for processing cord blood samples; S. Zhao (Hospital for Sick Children, Toronto, Ontario) for sorting; and the Dick lab and N. Iscove for critical review of the manuscript. Supported by The Stem Cell Network of National Centres of Excellence; the National Cancer Institute of Canada with funds from the Canadian Cancer Society and the Terry Fox Foundation; Genome Canada through the Ontario Genomics Institute; Ontario Cancer Research Network with funds from the province of Ontario; the Leukemia and Lymphoma Society; the Canadian Institutes for Health Research; and Canada Research.

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  1. Joby L McKenzie and Olga I Gan: These authors contributed equally to this manuscript.

Authors and Affiliations

  1. Division of Cell and Molecular Biology, University Health Network, Toronto, M5G 1L7, Ontario, Canada

    Joby L McKenzie, Olga I Gan, Monica Doedens, Jean C Y Wang & John E Dick

  2. Department of Molecular and Medical Genetics, University of Toronto, Toronto, M5G 1L7, Ontario, Canada

    Joby L McKenzie & John E Dick

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  1. Joby L McKenzie
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Contributions

J.L.M. and O.I.G. designed and did research, collected and analyzed data and wrote the paper; M.D. did research and collected data; J.C.Y.W. did research and wrote the paper; and J.E.D. designed research, analyzed data and wrote the paper.

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Correspondence to John E Dick.

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Supplementary information

Supplementary Fig. 1

Summary of the self-renewal properties of CD34+CD38lo and Lin− SRC. (PDF 103 kb)

Supplementary Fig. 2

Thirty-week multilineage engraftment from a mouse reconstituted by one transduced clone. (PDF 168 kb)

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McKenzie, J., Gan, O., Doedens, M. et al. Individual stem cells with highly variable proliferation and self-renewal properties comprise the human hematopoietic stem cell compartment. Nat Immunol 7, 1225–1233 (2006). https://doi.org/10.1038/ni1393

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