Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature volume 457, pages 92–96 (2009)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The calvarium endosteal niche is perivascular.
Figure 2: Engrafting HSPCs reach the endosteum.
Figure 3: Engraftment is initiated by asynchronous HSPC cell divisions.
Figure 4: Cell-dependent and niche-dependent HSPC localization.

Similar content being viewed by others

References

  1. Schofield, R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4, 7–25 (1978)

    CAS  Google Scholar 

  2. Xie, T. & Spradling, A. C. A niche maintaining germ line stem cells in the Drosophila ovary. Science 290, 328–330 (2000)

    Article  ADS  CAS  Google Scholar 

  3. Sipkins, D. A. et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 435, 969–973 (2005)

    Article  ADS  CAS  Google Scholar 

  4. Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003)

    Article  ADS  CAS  Google Scholar 

  5. Nilsson, S. K. et al. Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood 106, 1232–1239 (2005)

    Article  CAS  Google Scholar 

  6. Stier, S. et al. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J. Exp. Med. 201, 1781–1791 (2005)

    Article  CAS  Google Scholar 

  7. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003)

    Article  ADS  CAS  Google Scholar 

  8. Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004)

    Article  CAS  Google Scholar 

  9. 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)

    Article  CAS  Google Scholar 

  10. Nilsson, S. K., Johnston, H. M. & Coverdale, J. A. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood 97, 2293–2299 (2001)

    Article  CAS  Google Scholar 

  11. Lord, B. I., Testa, N. G. & Hendry, J. H. The relative spatial distributions of CFUs and CFUc in the normal mouse femur. Blood 46, 65–72 (1975)

    CAS  PubMed  Google Scholar 

  12. Taichman, R. S., Reilly, M. J. & Emerson, S. G. The Hematopoietic microenvironment: Osteoblasts and the hematopoietic microenvironment. Hematology 4, 421–426 (2000)

    Article  Google Scholar 

  13. Mayack, S. R. & Wagers, A. J. Osteolineage niche cells initiate hematopoietic stem cell mobilization. Blood 112, 519–531 (2008)

    Article  CAS  Google Scholar 

  14. Crock, H. V. The Blood Supply of the Lower Limb Bones in Man (E&S Livingstone LTD, 1967)

    Google Scholar 

  15. Kalajzic, Z. et al. Directing the expression of a green fluorescent protein transgene in differentiated osteoblasts: comparison between rat type I collagen and rat osteocalcin promoters. Bone 31, 654–660 (2002)

    Article  CAS  Google Scholar 

  16. Bryder, D., Rossi, D. J. & Weissman, I. L. Hematopoietic stem cells: the paradigmatic tissue-specific stem cell. Am. J. Pathol. 169, 338–346 (2006)

    Article  CAS  Google Scholar 

  17. Kiel, M. J. et al. Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU. Nature 449, 238–242 (2007)

    Article  ADS  CAS  Google Scholar 

  18. Abkowitz, J. L., Catlin, S. N., McCallie, M. T. & Guttorp, P. Evidence that the number of hematopoietic stem cells per animal is conserved in mammals. Blood 100, 2665–2667 (2002)

    Article  CAS  Google Scholar 

  19. Lewin, M. et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nature Biotechnol. 18, 410–414 (2000)

    Article  CAS  Google Scholar 

  20. Suzuki, N. et al. Combinatorial Gata2 and Sca1 expression defines hematopoietic stem cells in the bone marrow niche. Proc. Natl Acad. Sci. USA 103, 2202–2207 (2006)

    Article  ADS  CAS  Google Scholar 

  21. Adams, G. B. et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439, 599–603 (2006)

    Article  ADS  CAS  Google Scholar 

  22. Zhong, J. F., Zhan, Y., Anderson, W. F. & Zhao, Y. Murine hematopoietic stem cell distribution and proliferation in ablated and nonablated bone marrow transplantation. Blood 100, 3521–3526 (2002)

    Article  CAS  Google Scholar 

  23. Migliaccio, A. R., Carta, C. & Migliaccio, G. In vivo expansion of purified hematopoietic stem cells transplanted in nonablated W/Wv mice. Exp. Hematol. 27, 1655–1666 (1999)

    Article  CAS  Google Scholar 

  24. Nilsson, S. K., Dooner, M. S. & Quesenberry, P. J. Synchronized cell-cycle induction of engrafting long-term repopulating stem cells. Blood 90, 4646–4650 (1997)

    CAS  PubMed  Google Scholar 

  25. Forsberg, E. C., Serwold, T., Kogan, S., Weissman, I. L. & Passegue, E. New evidence supporting megakaryocyte-erythrocyte potential of flk2/flt3+ multipotent hematopoietic progenitors. Cell 126, 415–426 (2006)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. 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)

    Article  CAS  Google Scholar 

  28. 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)

    Article  ADS  CAS  Google Scholar 

  29. Calvi, L. M. et al. Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. J. Clin. Invest. 107, 277–286 (2001)

    Article  CAS  Google Scholar 

  30. Adams, G. B. et al. Therapeutic targeting of a stem cell niche. Nature Biotechnol. 25, 238–243 (2007)

    Article  CAS  Google Scholar 

  31. Zipfel, W. R., Williams, R. M. & Webb, W. W. Nonlinear magic: multiphoton microscopy in the biosciences. Nature Biotechnol. 21, 1369–1377 (2003)

    Article  CAS  Google Scholar 

  32. Veilleux, I., Spencer, J. A., Biss, D. P., Cote, D. & Lin, C. P. In vivo cell tracking with video rate multimodality laser scanning microscopy. IEEE JSTQE 14, 10–18 (2008)

    ADS  CAS  Google Scholar 

  33. Brennand, K., Huangfu, D. & Melton, D. All beta cells contribute equally to islet growth and maintenance. PLoS Biol. 5, e163 (2007)

    Article  Google Scholar 

Download references

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

  1. Daniel Côté

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

Authors and 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

Authors
  1. Cristina Lo Celso
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Heather E. Fleming
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juwell W. Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cher X. Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sam Miake-Lye
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joji Fujisaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniel Côté
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David W. Rowe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Charles P. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David T. Scadden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

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

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-9 with Legends and Supplementary Movie 1 Legend. (PDF 13921 kb)

Supplementary Movie 1

This file contains Supplementary Movie 1. (MOV 7538 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lo Celso, C., Fleming, H., Wu, J. et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 457, 92–96 (2009). https://doi.org/10.1038/nature07434

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07434

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing