Letter | Published:

Age-dependent modulation of vascular niches for haematopoietic stem cells

Nature volume 532, pages 380384 (21 April 2016) | Download Citation

  • A Corrigendum to this article was published on 14 September 2016

Abstract

Blood vessels define local microenvironments in the skeletal system, play crucial roles in osteogenesis and provide niches for haematopoietic stem cells1,2,3,4,5,6. The properties of niche-forming vessels and their changes in the ageing organism remain incompletely understood. Here we show that Notch signalling in endothelial cells leads to the expansion of haematopoietic stem cell niches in bone, which involves increases in CD31-positive capillaries and platelet-derived growth factor receptor-β (PDGFRβ)-positive perivascular cells, arteriole formation and elevated levels of cellular stem cell factor. Although endothelial hypoxia-inducible factor signalling promotes some of these changes, it fails to enhance vascular niche function because of a lack of arterialization and expansion of PDGFRβ-positive cells. In ageing mice, niche-forming vessels in the skeletal system are strongly reduced but can be restored by activation of endothelial Notch signalling. These findings indicate that vascular niches for haematopoietic stem cells are part of complex, age-dependent microenvironments involving multiple cell populations and vessel subtypes.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , & Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462 (2012)

  2. 2.

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

  3. 3.

    et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005)

  4. 4.

    , & Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 507, 323–328 (2014)

  5. 5.

    et al. Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature 526, 126–130 (2015)

  6. 6.

    , , & Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature 507, 376–380 (2014)

  7. 7.

    et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502, 637–643 (2013)

  8. 8.

    , & Inhibition of gap junction communication at ectopic Eph/ephrin boundaries underlies craniofrontonasal syndrome. PLoS Biol. 4, e315 (2006)

  9. 9.

    et al. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev. 13, 295–306 (1999)

  10. 10.

    et al. Sox17 is indispensable for acquisition and maintenance of arterial identity. Nature Commun. 4, 2609 (2013)

  11. 11.

    & Molecular regulation of angiogenesis and lymphangiogenesis. Nature Rev. Mol. Cell Biol. 8, 464–478 (2007)

  12. 12.

    Mechanisms of angiogenesis and arteriogenesis. Nature Med. 6, 389–395 (2000)

  13. 13.

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

  14. 14.

    , , , & Role of PDGF-B and PDGFR-β in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126, 3047–3055 (1999)

  15. 15.

    et al. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol. 5, e201 (2007)

  16. 16.

    , , , & The aging of hematopoietic stem cells. Nature Med. 2, 1011–1016 (1996)

  17. 17.

    et al. Aging reduces skeletal blood flow, endothelium-dependent vasodilation, and NO bioavailability in rats. J. Bone Miner. Res. 22, 1280–1288 (2007)

  18. 18.

    , , & Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-γ2 transcription factor and TGF-beta/BMP signaling pathways. Aging Cell 3, 379–389 (2004)

  19. 19.

    et al. Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell 63, 213–224 (1990)

  20. 20.

    et al. Mapping the consequence of Notch1 proteolysis in vivo with NIP-CRE. Development 134, 535–544 (2007)

  21. 21.

    , , , & A global double-fluorescent Cre reporter mouse. Genesis 45, 593–605 (2007)

  22. 22.

    et al. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. Mol. Cell. Biol. 21, 7403–7415 (2001)

  23. 23.

    & Regulation of vascular morphogenesis by Notch signaling. Genes Dev. 21, 2511–2524 (2007)

  24. 24.

    Targeting HIF-1 for cancer therapy. Nature Rev. Cancer 3, 721–732 (2003)

  25. 25.

    , , & Coronary arteries form by developmental reprogramming of venous cells. Nature 464, 549–553 (2010)

  26. 26.

    et al. Arteries are formed by vein-derived endothelial tip cells. Nature Commun. 5, 5758 (2014)

  27. 27.

    & Steel factor and c-kit regulate cell-matrix adhesion. Blood 83, 1033–1038 (1994)

  28. 28.

    et al. Membrane-bound Steel factor induces more persistent tyrosine kinase activation and longer life span of c-kit gene-encoded protein than its soluble form. Blood 85, 641–649 (1995)

  29. 29.

    et al. Endothelial Jagged-1 is necessary for homeostatic and regenerative hematopoiesis. Cell Reports 4, 1022–1034 (2013)

  30. 30.

    , , , & Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells. J. Exp. Med. 208, 2691–2703 (2011)

  31. 31.

    et al. Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision. Int. Immunol. 14, 637–645 (2002)

  32. 32.

    et al. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465, 483–486 (2010)

  33. 33.

    et al. Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun. Nature Neurosci. 13, 1365–1372 (2010)

  34. 34.

    et al. Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J. Exp. Med. 205, 2515–2523 (2008)

  35. 35.

    et al. Loss of HIF-1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 6, 485–495 (2004)

  36. 36.

    , , & Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc. Natl Acad. Sci. USA 98, 1583–1588 (2001)

  37. 37.

    , , & Notch signaling controls multiple steps of pancreatic differentiation. Proc. Natl Acad. Sci. USA 100, 14920–14925 (2003)

  38. 38.

    et al. Pericytes regulate the blood–brain barrier. Nature 468, 557–561 (2010)

  39. 39.

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

  40. 40.

    et al. FGF-2 expands murine hematopoietic stem and progenitor cells via proliferation of stromal cells, c-Kit activation, and CXCL12 down-regulation. Blood 120, 1843–1855 (2012)

  41. 41.

    , & Characterization of mouse hematopoietic stem and progenitor cells. Curr. Protoc. Immunol. 22, 22B.2.1–22B.2.31 (2008)

  42. 42.

    , , , & Age-dependent response of murine female bone marrow cells to hyperbaric oxygen. Biogerontology 13, 287–297 (2012)

Download references

Acknowledgements

We thank M. Schiller for technical assistance, A. Starsichova for help with bone sample processing, M. Stehling for fluorescence-activated cell sorting (FACS), S. Volkery for microscopy, and M. Vanlandewijck and K. Nahar for help with PdgfbiOE-EC bones. Funding was provided by the Max Planck Society, the University of Münster, the DFG cluster of excellence ‘Cells in Motion’, and the European Research Council (AdG 339409 ‘AngioBone’). This research was partly supported by a joint grant from the Ministry of Science, Technology & Space, Israel, DKFZ Germany, ERC AdG 294556 ‘BBBarrier’, the Knut and Alice Wallenberg Foundation and the Swedish Cancer Foundation.

Author information

Affiliations

  1. Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, D-48149 Münster, Germany

    • Anjali P. Kusumbe
    • , Saravana K. Ramasamy
    • , Urs H. Langen
    •  & Ralf H. Adams
  2. Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel

    • Tomer Itkin
    •  & Tsvee Lapidot
  3. Vascular Biology Program, Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden

    • Maarja Andaloussi Mäe
    •  & Christer Betsholtz
  4. Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Scheeles väg 2, SE-171 77 Stockholm, Sweden

    • Christer Betsholtz

Authors

  1. Search for Anjali P. Kusumbe in:

  2. Search for Saravana K. Ramasamy in:

  3. Search for Tomer Itkin in:

  4. Search for Maarja Andaloussi Mäe in:

  5. Search for Urs H. Langen in:

  6. Search for Christer Betsholtz in:

  7. Search for Tsvee Lapidot in:

  8. Search for Ralf H. Adams in:

Contributions

A.P.K., S.K.R. and R.H.A. designed experiments and interpreted results. A.P.K. and S.K.R. organized and conducted most experiments, including generation and characterization of mouse lines, imaging, flow cytometric analysis and transplantations. T.I. and T.L. designed and performed transplantation experiments. M.A.M. and C.B. generated and provided samples from PdgfbiOE-EC mice. A.P.K and U.H.L. analysed Efnb2 and NICD-Cre mice. A.P.K., S.K.R. and R.H.A. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Anjali P. Kusumbe or Ralf H. Adams.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Table 1, a list of antibodies.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature17638

Further reading

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.