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:

CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance

Subjects

Abstract

Haematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation and trafficking. Endosteal osteoblasts1,2 and perivascular stromal cells including endothelial cells3, CXCL12-abundant reticular cells4,5, leptin-receptor-positive stromal cells6, and nestin–green fluorescent protein (GFP)-positive mesenchymal progenitors7 have all been implicated in HSC maintenance. However, it is unclear whether specific haematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (chemokine (C–X–C motif) ligand 12) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations7,8,9,10,11. Here we selectively deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from osterix-expressing stromal cells, which include CXCL12-abundant reticular cells and osteoblasts, results in constitutive HPC mobilization and a loss of B-lymphoid progenitors, but HSC function is normal. Cxcl12 deletion from endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12 from nestin-negative mesenchymal progenitors using Prx1–cre (Prx1 also known as Prrx1) is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B-lymphoid progenitors and retains HPCs in the bone marrow, and that expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, supports HSCs.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Targeting Cxcl12 deletion in bone marrow stromal cell populations.
Figure 2: Deletion of Cxcl12 in defined stromal cell population results in the selective loss of HSCs and lymphoid progenitors.
Figure 3: Deletion of Cxcl12 in defined stromal cell populations results in HPC mobilization and a selective loss of repopulating activity and HSC quiescence.
Figure 4: Prx1–cre differentially targets a PDGFRα + SCA1 + CXCL12-expressing mesenchymal progenitor cell population.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The RNA expression profiling data have been deposited in Gene Expression Omnibus under accession number GSE43613.

References

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

    Article  CAS  ADS  Google Scholar 

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

    Article  CAS  ADS  Google Scholar 

  3. Hooper, A. T. et al. Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells. Cell Stem Cell 4, 263–274 (2009)

    Article  CAS  Google Scholar 

  4. Omatsu, Y. et al. The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity 33, 387–399 (2010)

    Article  CAS  Google Scholar 

  5. Sugiyama, T., Kohara, H., Noda, M. & Nagasawa, T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25, 977–988 (2006)

    Article  CAS  Google Scholar 

  6. Ding, L., Saunders, T. L., Enikolopov, G. & Morrison, S. J. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462 (2012)

    Article  CAS  ADS  Google Scholar 

  7. Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010)

    Article  ADS  Google Scholar 

  8. Peled, A. et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 283, 845–848 (1999)

    Article  CAS  ADS  Google Scholar 

  9. Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007)

    Article  CAS  Google Scholar 

  10. Semerad, C. L. et al. G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 106, 3020–3027 (2005)

    Article  CAS  Google Scholar 

  11. Tokoyoda, K., Egawa, T., Sugiyama, T., Choi, B. I. & Nagasawa, T. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 20, 707–718 (2004)

    Article  CAS  Google Scholar 

  12. Ara, T. et al. A role of CXC chemokine ligand 12/stromal cell-derived factor-1/pre-B cell growth stimulating factor and its receptor CXCR4 in fetal and adult T cell development in vivo. J. Immunol. 170, 4649–4655 (2003)

    Article  CAS  Google Scholar 

  13. Bonig, H., Priestley, G. V., Nilsson, L. M., Jiang, Y. & Papayannopoulou, T. PTX-sensitive signals in bone marrow homing of fetal and adult hematopoietic progenitor cells. Blood 104, 2299–2306 (2004)

    Article  CAS  Google Scholar 

  14. Kawabata, K. et al. A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution. Proc. Natl Acad. Sci. USA 96, 5663–5667 (1999)

    Article  CAS  ADS  Google Scholar 

  15. Nie, Y., Han, Y. C. & Zou, Y. R. CXCR4 is required for the quiescence of primitive hematopoietic cells. J. Exp. Med. 205, 777–783 (2008)

    Article  CAS  Google Scholar 

  16. Tzeng, Y. S. et al. Loss of Cxcl12/Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression. Blood 117, 429–439 (2011)

    Article  CAS  Google Scholar 

  17. Maes, C. et al. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev. Cell 19, 329–344 (2010)

    Article  CAS  Google Scholar 

  18. Logan, M. et al. Expression of Cre recombinase in the developing mouse limb bud driven by a Prxl enhancer. Genesis 33, 77–80 (2002)

    Article  CAS  Google Scholar 

  19. 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 

  20. Ding, L. & Morrison, S. J. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Naturehttp://dx.doi.org/10.1038/nature11885 (2013)

  21. Foudi, A. et al. Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nature Biotechnol. 27, 84–90 (2009)

    Article  CAS  Google Scholar 

  22. Nagasawa, T. et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382, 635–638 (1996)

    Article  CAS  ADS  Google Scholar 

  23. Morikawa, S. et al. Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. J. Exp. Med. 206, 2483–2496 (2009)

    Article  CAS  Google Scholar 

  24. Zhan, M. & Han, Z. C. Hemangiopoietin inhibits apoptosis of MO7e leukemia cells through phosphatidylinositol 3-kinase-AKT pathway. Biochem. Biophys. Res. Commun. 317, 198–204 (2004)

    Article  CAS  Google Scholar 

  25. Lehmann, S. et al. Common deleted genes in the 5q- syndrome: thrombocytopenia and reduced erythroid colony formation in SPARC null mice. Leukemia 21, 1931–1936 (2007)

    Article  CAS  Google Scholar 

  26. Rodda, S. J. & McMahon, A. P. Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development 133, 3231–3244 (2006)

    Article  CAS  Google Scholar 

  27. Zhang, M. et al. Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J. Biol. Chem. 277, 44005–44012 (2002)

    Article  CAS  Google Scholar 

  28. Kisanuki, Y. Y. et al. Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. Dev. Biol. 230, 230–242 (2001)

    Article  CAS  Google Scholar 

  29. Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nature Neurosci. 13, 133–140 (2010)

    Article  CAS  Google Scholar 

  30. Lakso, M. et al. Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc. Natl Acad. Sci. USA 93, 5860–5865 (1996)

    Article  CAS  ADS  Google Scholar 

  31. Semerad, C. L., Liu, F., Gregory, A. D., Stumpf, K. & Link, D. C. G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity 17, 413–423 (2002)

    Article  CAS  Google Scholar 

  32. Churukian, C. Lillie’s oil red O method for neutral lipids. J. Histotechnol. 22, 309–311 (1999)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Woloszynek, F. Liu, A. Khalaf and M. Romine for technical assistance; G. Callis, S. Oh and M. Vig for technical advice; J. Tucker-Davis for animal care; and T. Clemens for the Oc–cre mice. This work was supported by NIH grants RO1 HL60772 (D.C.L.) and F30 HL097423 (A.G.).

Author information

Authors and Affiliations

Authors

Contributions

A.G. and Y.-M.S.H. designed and performed the research, analysed the data and wrote the manuscript. L.G.S., J.N.B. and R.B.D. performed experiments characterizing haematopoiesis in the conditional Cxcl12-deficient mice. M.J.C. designed and cloned the CXCL12 conditional knockout construct. D.C.L. supervised all of the research and edited the manuscript, which was approved by all co-authors.

Corresponding author

Correspondence to Daniel C. Link.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-8 and Supplementary Tables 1-2. (PDF 9655 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Greenbaum, A., Hsu, YM., Day, R. et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495, 227–230 (2013). https://doi.org/10.1038/nature11926

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11926

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

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