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Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche

Nature volume 457, pages 9296 (01 January 2009) | Download Citation

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Abstract

Stem cells reside in a specialized, regulatory environment termed the niche that dictates how they generate, maintain and repair tissues1,2. We have previously documented that transplanted haematopoietic stem and progenitor cell populations localize to subdomains of bone-marrow microvessels where the chemokine CXCL12 is particularly abundant3. Using a combination of high-resolution confocal microscopy and two-photon video imaging of individual haematopoietic cells in the calvarium bone marrow of living mice over time, we examine the relationship of haematopoietic stem and progenitor cells to blood vessels, osteoblasts and endosteal surface as they home and engraft in irradiated and c-Kit-receptor-deficient recipient mice. Osteoblasts were enmeshed in microvessels and relative positioning of stem/progenitor cells within this complex tissue was nonrandom and dynamic. Both cell autonomous and non-autonomous factors influenced primitive cell localization. Different haematopoietic cell subsets localized to distinct locations according to the stage of differentiation. When physiological challenges drove either engraftment or expansion, bone-marrow stem/progenitor cells assumed positions in close proximity to bone and osteoblasts. Our analysis permits observing in real time, at a single cell level, processes that previously have been studied only by their long-term outcome at the organismal level.

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Acknowledgements

We thank E. Schipani for providing the PPR mice. We are grateful for help and advice from A. Catic, L. Purton, V. Janzen, G. Adams, J. Spencer, J. Runnels and P. O’Donovan. We thank Y. Tang for the mice husbandry care; D. Dombkowski, L. Prickett and K. Folz-Donahue for cell sorting expertise; R. Klein and K. Chomsky-Higgins for technical assistance; and C. Pasker, V. Shannon, M. Indico Miklosik and D. Machon for administrative assistance. C.L.C. was funded by EMBO and HFSP. The project was funded by the National Institutes of Health (to D.T.S. and C.P.L.), the Harvard Stem Cell Institute (to C.P.L.) and philanthropic sources (to D.T.S. and C.L.C.).

Author information

Author notes

    • Daniel Côté

    Present address: Centre de Recherche Université Laval Robert-Giffard, Département de Physique, Université Laval, Québec, Québec G1J 2G3, Canada.

Affiliations

  1. Center for Regenerative Medicine and,

    • Cristina Lo Celso
    • , Heather E. Fleming
    • , Cher X. Zhao
    • , Sam Miake-Lye
    •  & David T. Scadden
  2. Cancer Center,

    • David T. Scadden
  3. Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA

    • Juwell W. Wu
    • , Joji Fujisaki
    • , Daniel Côté
    •  & Charles P. Lin
  4. Harvard Stem Cell Institute, 42 Church Street, Cambridge, Massachusetts 02138, USA

    • Cristina Lo Celso
    • , Heather E. Fleming
    • , Juwell W. Wu
    • , Cher X. Zhao
    • , Joji Fujisaki
    • , Charles P. Lin
    •  & David T. Scadden
  5. University of Connecticut Health Center, 663 Farmington Avenue, Farmington, Connecticut 06030, USA

    • David W. Rowe
  6. Department of Stem Cell and Regenerative Biology, Harvard University, 42 Church Street, Cambridge, Massachusetts 02138, USA

    • David T. Scadden

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Competing interests

D.T.S. is a consultant and stockholder for Fate Therapeusis.

Corresponding authors

Correspondence to Charles P. Lin or David T. Scadden.

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DOI

https://doi.org/10.1038/nature07434

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