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.

  • Review Article
  • Published:

Hematopoietic stem cell niche maintenance during homeostasis and regeneration

Nature Medicine volume 20, pages 833–846 (2014)Cite this article

Subjects

Abstract

The bone marrow niche has mystified scientists for many years, leading to widespread investigation to shed light into its molecular and cellular composition. Considerable efforts have been devoted toward uncovering the regulatory mechanisms of hematopoietic stem cell (HSC) niche maintenance. Recent advances in imaging and genetic manipulation of mouse models have allowed the identification of distinct vascular niches that have been shown to orchestrate the balance between quiescence, proliferation and regeneration of the bone marrow after injury. Here we highlight the recently discovered intrinsic mechanisms, microenvironmental interactions and communication with surrounding cells involved in HSC regulation, during homeostasis and in regeneration after injury and discuss their implications for regenerative therapy.

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: Key cell types involved in regulating HSC maintenance.
Figure 2: Expanding the endosteal zone.
Figure 3: The vascular niche's effect on regeneration.
Figure 4: The effects of aging on HSC behavior.

Similar content being viewed by others

References

  1. Lucas, D. et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat. Med. 19, 695–703 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pietras, E.M. et al. Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons. J. Exp. Med. 211, 245–262 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lymperi, S., Ferraro, F. & Scadden, D.T. The HSC niche concept has turned 31. Has our knowledge matured? Ann. NY Acad. Sci. 1192, 12–18 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Wang, L.D. & Wagers, A.J. Dynamic niches in the origination and differentiation of hematopoietic stem cells. Nat. Rev. Mol. Cell Biol. 12, 643–655 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Warr, M.R., Pietras, E.M. & Passegue, E. Mechanisms controlling hematopoietic stem cell functions during normal hematopoiesis and hematological malignancies. Wiley Interdiscip. Rev. Syst. Biol. Med. 3, 681–701 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Morrison, S.J. & Scadden, D.T. The bone marrow niche for hematopoietic stem cells. Nature 505, 327–334 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Adamo, L. et al. Biomechanical forces promote embryonic haematopoiesis. Nature 459, 1131–1135 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shin, J.W. et al. Contractile forces sustain and polarize hematopoiesis from stem and progenitor cells. Cell Stem Cell 14, 81–93 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Passegué, E., Wagers, A.J., Giuriato, S., Anderson, W.C. & Weissman, I.L. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J. Exp. Med. 202, 1599–1611 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Essers, M.A. et al. IFNα activates dormant haematopoietic stem cells in vivo. Nature 458, 904–908 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Baldridge, M.T., King, K.Y., Boles, N.C., Weksberg, D.C. & Goodell, M.A. Quiescent haematopoietic stem cells are activated by IFN-γ in response to chronic infection. Nature 465, 793–797 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cao, X. et al. Irradiation induces bone injury by damaging bone marrow microenvironment for stem cells. Proc. Natl. Acad. Sci. USA 108, 1609–1614 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Özcan, M.A., Ilhan, O., Ozcebe, O.I., Nalcaci, M. & Gulbas, Z. Review of therapeutic options and the management of patients with myelodysplastic syndromes. Expert Rev. Hematol. 6, 165–189 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Doulatov, S., Notta, F., Laurenti, E. & Dick, J.E. Hematopoiesis: a human perspective. Cell Stem Cell 10, 120–136 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Pereira, C.F. et al. Induction of a hemogenic program in mouse fibroblasts. Cell Stem Cell 13, 205–218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Riddell, J. et al. Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell 157, 549–564 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sandler, V. et al. Reprogramming human endothelial to hematopoietic cells requires vascular induction. Nature 10.1038/nature13547 (2 July 2014).

  19. Friedenstein, A.J., Chailakhyan, R.K., Latsinik, N.V., Panasyuk, A.F. & Keiliss-Borok, I.V. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 17, 331–340 (1974).

    Article  CAS  PubMed  Google Scholar 

  20. Song, J. et al. An in vivo model to study and manipulate the hematopoietic stem cell niche. Blood 115, 2592–2600 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Pinho, S. et al. PDGFRα and CD51 mark human nestin+ sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion. J. Exp. Med. 210, 1351–1367 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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  PubMed  Google Scholar 

  25. Greenbaum, A. et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495, 227–230 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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  PubMed  PubMed Central  Google Scholar 

  27. Park, D. et al. Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell 10, 259–272 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Joseph, C. et al. Deciphering hematopoietic stem cells in their niches: a critical appraisal of genetic models, lineage tracing, and imaging strategies. Cell Stem Cell 13, 520–533 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Ding, L. & Morrison, S.J. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495, 231–235 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mizoguchi, T. et al. Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development. Dev. Cell 29, 340–349 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhou, B.O., Yue, R., Murphy, M.M., Peyer, J.G. & Morrison, S.J. Leptin-receptor–expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 10.1016/j.stem.2014.06.008 (19 June 2014).

  33. Nolan, D.J. et al. Molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration. Dev. Cell 26, 204–219 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Kobayashi, H. et al. Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nat. Cell Biol. 12, 1046–1056 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Krause, D.S., Scadden, D.T. & Preffer, F.I. The hematopoietic stem cell niche—home for friend and foe? Cytometry B Clin. Cytom. 84, 7–20 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Kennedy, M. et al. A common precursor for primitive erythropoiesis and definitive haematopoiesis. Nature 386, 488–493 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1–deficient mice. Nature 376, 62–66 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Ono, N. et al. Vasculature-associated cells expressing nestin in developing bones encompass early cells in the osteoblast and endothelial lineage. Dev. Cell 29, 330–339 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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  PubMed  Google Scholar 

  40. Doan, P.L. et al. Epidermal growth factor regulates hematopoietic regeneration after radiation injury. Nat. Med. 19, 295–304 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Himburg, H.A. et al. Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche. Cell Reports 2, 964–975 (2012).

    Article  CAS  PubMed  Google Scholar 

  42. 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  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  45. Liu, Y. et al. Osterix-Cre labeled progenitor cells contribute to the formation and maintenance of the bone marrow stroma. PLoS ONE 8, e71318 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Méndez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P.S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Katayama, Y. et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407–421 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Yamazaki, S. et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147, 1146–1158 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Chow, A. et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J. Exp. Med. 208, 261–271 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Christopher, M.J., Rao, M., Liu, F., Woloszynek, J.R. & Link, D.C. Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice. J. Exp. Med. 208, 251–260 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Winkler, I.G. et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 116, 4815–4828 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Lucas, D. et al. Norepinephrine reuptake inhibition promotes mobilization in mice: potential impact to rescue low stem cell yields. Blood 119, 3962–3965 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460, 259–263 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Miyamoto, K. et al. Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization. J. Exp. Med. 208, 2175–2181 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kollet, O. et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat. Med. 12, 657–664 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Lin, H. The stem-cell niche theory: lessons from flies. Nat. Rev. Genet. 3, 931–940 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  58. Schajnovitz, A. et al. CXCL12 secretion by bone marrow stromal cells is dependent on cell contact and mediated by connexin-43 and connexin-45 gap junctions. Nat. Immunol. 12, 391–398 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Pajcini, K.V., Speck, N.A. & Pear, W.S. Notch signaling in mammalian hematopoietic stem cells. Leukemia 25, 1525–1532 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bigas, A. & Espinosa, L. Hematopoietic stem cells: to be or Notch to be. Blood 119, 3226–3235 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Oh, P. et al. In vivo mapping of notch pathway activity in normal and stress hematopoiesis. Cell Stem Cell 13, 190–204 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Varnum-Finney, B. et al. Notch2 governs the rate of generation of mouse long- and short-term repopulating stem cells. J. Clin. Invest. 121, 1207–1216 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Maillard, I. et al. Canonical Notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell 2, 356–366 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mercher, T. et al. Notch signaling specifies megakaryocyte development from hematopoietic stem cells. Cell Stem Cell 3, 314–326 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  66. Mancini, S.J. et al. Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation. Blood 105, 2340–2342 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Lee, S.U. et al. LRF-mediated Dll4 repression in erythroblasts is necessary for hematopoietic stem cell maintenance. Blood 121, 918–929 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Oyama, T. et al. Mastermind-like 1 (MamL1) and mastermind-like 3 (MamL3) are essential for Notch signaling in vivo. Development 138, 5235–5246 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Malhotra, S. & Kincade, P.W. Wnt-related molecules and signaling pathway equilibrium in hematopoiesis. Cell Stem Cell 4, 27–36 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Willert, K. et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448–452 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Reya, T. et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423, 409–414 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Scheller, M. et al. Hematopoietic stem cell and multilineage defects generated by constitutive β-catenin activation. Nat. Immunol. 7, 1037–1047 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Kirstetter, P., Anderson, K., Porse, B.T., Jacobsen, S.E. & Nerlov, C. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat. Immunol. 7, 1048–1056 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Luis, T.C. et al. Wnt3a deficiency irreversibly impairs hematopoietic stem cell self-renewal and leads to defects in progenitor cell differentiation. Blood 113, 546–554 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Fleming, H.E. et al. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell 2, 274–283 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Cobas, M. et al. β-catenin is dispensable for hematopoiesis and lymphopoiesis. J. Exp. Med. 199, 221–229 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhao, C. et al. Loss of β-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 12, 528–541 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Koch, U. et al. Simultaneous loss of β- and γ-catenin does not perturb hematopoiesis or lymphopoiesis. Blood 111, 160–164 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Jeannet, G. et al. Long-term, multilineage hematopoiesis occurs in the combined absence of β-catenin and γ-catenin. Blood 111, 142–149 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Staal, F.J. & Luis, T.C. Wnt signaling in hematopoiesis: crucial factors for self-renewal, proliferation, and cell fate decisions. J. Cell. Biochem. 109, 844–849 (2010).

    CAS  PubMed  Google Scholar 

  81. Nemeth, M.J., Topol, L., Anderson, S.M., Yang, Y. & Bodine, D.M. Wnt5a inhibits canonical Wnt signaling in hematopoietic stem cells and enhances repopulation. Proc. Natl. Acad. Sci. USA 104, 15436–15441 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Povinelli, B.J. & Nemeth, M.J. Wnt5a regulates hematopoietic stem cell proliferation and repopulation through the Ryk receptor. Stem Cells 32, 105–115 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sugimura, R. et al. Noncanonical Wnt signaling maintains hematopoietic stem cells in the niche. Cell 150, 351–365 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Luis, T.C. et al. Canonical Wnt signaling regulates hematopoiesis in a dosage-dependent fashion. Cell Stem Cell 9, 345–356 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Haug, J.S. et al. N-cadherin expression level distinguishes reserved versus primed states of hematopoietic stem cells. Cell Stem Cell 2, 367–379 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Hosokawa, K. et al. Cadherin-based adhesion is a potential target for niche manipulation to protect hematopoietic stem cells in adult bone marrow. Cell Stem Cell 6, 194–198 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Kiel, M.J., Acar, M., Radice, G.L. & Morrison, S.J. Hematopoietic stem cells do not depend on N-cadherin to regulate their maintenance. Cell Stem Cell 4, 170–179 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Greenbaum, A.M., Revollo, L.D., Woloszynek, J.R., Civitelli, R. & Link, D.C. N-cadherin in osteolineage cells is not required for maintenance of hematopoietic stem cells. Blood 120, 295–302 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Bromberg, O. et al. Osteoblastic N-cadherin is not required for microenvironmental support and regulation of hematopoietic stem and progenitor cells. Blood 120, 303–313 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Challen, G.A., Boles, N.C., Chambers, S.M. & Goodell, M.A. Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-β1. Cell Stem Cell 6, 265–278 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Brenet, F., Kermani, P., Spektor, R., Rafii, S. & Scandura, J.M. TGFβ restores hematopoietic homeostasis after myelosuppressive chemotherapy. J. Exp. Med. 210, 623–639 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Miharada, K. et al. Cripto regulates hematopoietic stem cells as a hypoxic-niche–related factor through cell surface receptor GRP78. Cell Stem Cell 9, 330–344 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. 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  PubMed  Google Scholar 

  94. Istvanffy, R. et al. Stromal pleiotrophin regulates repopulation behavior of hematopoietic stem cells. Blood 118, 2712–2722 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Ghiaur, G. et al. Regulation of human hematopoietic stem cell self-renewal by the microenvironment's control of retinoic acid signaling. Proc. Natl. Acad. Sci. USA 110, 16121–16126 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Spoorendonk, K.M. et al. Retinoic acid and Cyp26b1 are critical regulators of osteogenesis in the axial skeleton. Development 135, 3765–3774 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Nombela-Arrieta, C. et al. Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment. Nat. Cell Biol. 15, 533–543 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ellis, S.L. et al. The relationship between bone, hemopoietic stem cells, and vasculature. Blood 118, 1516–1524 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Guezguez, B. et al. Regional localization within the bone marrow influences the functional capacity of human HSCs. Cell Stem Cell 13, 175–189 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. Lo Celso, C. et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 457, 92–96 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Lewandowski, D. et al. In vivo cellular imaging pinpoints the role of reactive oxygen species in the early steps of adult hematopoietic reconstitution. Blood 115, 443–452 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Wang, L. et al. Identification of a clonally expanding haematopoietic compartment in bone marrow. EMBO J. 32, 219–230 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Signer, R.A. & Morrison, S.J. Mechanisms that regulate stem cell aging and life span. Cell Stem Cell 12, 152–165 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Suda, T., Takubo, K. & Semenza, G.L. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell 9, 298–310 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Mauch, P. et al. Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy. Int. J. Radiat. Oncol. Biol. Phys. 31, 1319–1339 (1995).

    Article  CAS  PubMed  Google Scholar 

  106. Sokolov, M. & Neumann, R. Lessons learned about human stem cell responses to ionizing radiation exposures: a long road still ahead of us. Int. J. Mol. Sci. 14, 15695–15723 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Becker, D. et al. Response of human hematopoietic stem and progenitor cells to energetic carbon ions. Int. J. Radiat. Biol. 85, 1051–1059 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Katoh, O. et al. Vascular endothelial growth factor inhibits apoptotic death in hematopoietic cells after exposure to chemotherapeutic drugs by inducing MCL1 acting as an antiapoptotic factor. Cancer Res. 58, 5565–5569 (1998).

    CAS  PubMed  Google Scholar 

  109. Geiger, H. et al. Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. Nat. Med. 18, 1123–1129 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Iwasaki, H., Arai, F., Kubota, Y., Dahl, M. & Suda, T. Endothelial protein C receptor–expressing hematopoietic stem cells reside in the perisinusoidal niche in fetal liver. Blood 116, 544–553 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Johnson, S.M. et al. Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. J. Clin. Invest. 120, 2528–2536 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Marone, M. et al. Survival and cell cycle control in early hematopoiesis: role of bcl-2, and the cyclin dependent kinase inhibitors P27 and P21. Leuk. Lymphoma 43, 51–57 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Milyavsky, M. et al. A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independent role for p53 in self-renewal. Cell Stem Cell 7, 186–197 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Lange, C. et al. Radiation rescue: mesenchymal stromal cells protect from lethal irradiation. PLoS ONE 6, e14486 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Jung, H. et al. TXNIP maintains the hematopoietic cell pool by switching the function of p53 under oxidative stress. Cell Metab. 18, 75–85 (2013).

    Article  CAS  PubMed  Google Scholar 

  116. Ray, P.D., Huang, B.W. & Tsuji, Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell. Signal. 24, 981–990 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Ito, K. et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat. Med. 12, 446–451 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Yahata, T. et al. Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells. Blood 118, 2941–2950 (2011).

    Article  CAS  PubMed  Google Scholar 

  119. Koh, A.J. et al. An irradiation-altered bone marrow microenvironment impacts anabolic actions of PTH. Endocrinology 152, 4525–4536 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. MacVittie, T.J. & Farese, A.M. Cytokine-based treatment of radiation injury: potential benefits after low-level radiation exposure. Mil. Med. 167, 68–70 (2002).

    Article  PubMed  Google Scholar 

  121. Drouet, M. et al. Single administration of stem cell factor, FLT-3 ligand, megakaryocyte growth and development factor, and interleukin-3 in combination soon after irradiation prevents nonhuman primates from myelosuppression: long-term follow-up of hematopoiesis. Blood 103, 878–885 (2004).

    Article  CAS  PubMed  Google Scholar 

  122. Hérodin, F., Bourin, P., Mayol, J.F., Lataillade, J.J. & Drouet, M. Short-term injection of antiapoptotic cytokine combinations soon after lethal gamma irradiation promotes survival. Blood 101, 2609–2616 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Doan, P.L. et al. Tie2+ bone marrow endothelial cells regulate hematopoietic stem cell regeneration following radiation injury. Stem Cells 31, 327–337 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Katoh, O., Tauchi, H., Kawaishi, K., Kimura, A. & Satow, Y. Expression of the vascular endothelial growth factor (VEGF) receptor gene, KDR, in hematopoietic cells and inhibitory effect of VEGF on apoptotic cell death caused by ionizing radiation. Cancer Res. 55, 5687–5692 (1995).

    CAS  PubMed  Google Scholar 

  125. Gerber, H.P. et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417, 954–958 (2002).

    Article  CAS  PubMed  Google Scholar 

  126. Zhao, M. et al. FGF signaling facilitates postinjury recovery of mouse hematopoietic system. Blood 120, 1831–1842 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. de Bruin, A.M., Demirel, O., Hooibrink, B., Brandts, C.H. & Nolte, M.A. Interferon-γ impairs proliferation of hematopoietic stem cells in mice. Blood 121, 3578–3585 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Lam, B.S., Cunningham, C. & Adams, G.B. Pharmacologic modulation of the calcium-sensing receptor enhances hematopoietic stem cell lodgment in the adult bone marrow. Blood 117, 1167–1175 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Sreeramkumar, V. et al. Coordinated and unique functions of the E-selectin ligand ESL-1 during inflammatory and hematopoietic recruitment in mice. Blood 122, 3993–4001 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Nakamura-Ishizu, A. et al. Extracellular matrix protein tenascin-C is required in the bone marrow microenvironment primed for hematopoietic regeneration. Blood 119, 5429–5437 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Smith-Berdan, S. et al. Robo4 cooperates with CXCR4 to specify hematopoietic stem cell localization to bone marrow niches. Cell Stem Cell 8, 72–83 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Chow, A. et al. CD169+ macrophages provide a niche promoting erythropoiesis under homeostasis and stress. Nat. Med. 19, 429–436 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ramos, P. et al. Macrophages support pathological erythropoiesis in polycythemia vera and β-thalassemia. Nat. Med. 19, 437–445 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Pitchford, S.C., Lodie, T. & Rankin, S.M. VEGFR1 stimulates a CXCR4-dependent translocation of megakaryocytes to the vascular niche, enhancing platelet production in mice. Blood 120, 2787–2795 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. Gars, E. & Rafii, S. It takes 2 to thrombopoies in the vascular niche. Blood 120, 2775–2776 (2012).

    Article  CAS  PubMed  Google Scholar 

  136. Dykstra, B., Olthof, S., Schreuder, J., Ritsema, M. & de Haan, G. Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells. J. Exp. Med. 208, 2691–2703 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Sudo, K., Ema, H., Morita, Y. & Nakauchi, H. Age-associated characteristics of murine hematopoietic stem cells. J. Exp. Med. 192, 1273–1280 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Geiger, H., Koehler, A. & Gunzer, M. Stem cells, aging, niche, adhesion and Cdc42: a model for changes in cell-cell interactions and hematopoietic stem cell aging. Cell Cycle 6, 884–887 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Morrison, S.J., Wandycz, A.M., Akashi, K., Globerson, A. & Weissman, I.L. The aging of hematopoietic stem cells. Nat. Med. 2, 1011–1016 (1996).

    Article  CAS  PubMed  Google Scholar 

  140. Chen, J., Astle, C.M. & Harrison, D.E. Development and aging of primitive hematopoietic stem cells in BALB/cBy mice. Exp. Hematol. 27, 928–935 (1999).

    Article  CAS  PubMed  Google Scholar 

  141. Liang, Y., Van Zant, G. & Szilvassy, S.J. Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 106, 1479–1487 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Rossi, D.J. et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc. Natl. Acad. Sci. USA 102, 9194–9199 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Beerman, I. et al. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc. Natl. Acad. Sci. USA 107, 5465–5470 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Florian, M.C. et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 10, 520–530 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Miller, J.P. & Allman, D. Linking age-related defects in B lymphopoiesis to the aging of hematopoietic stem cells. Semin. Immunol. 17, 321–329 (2005).

    Article  CAS  PubMed  Google Scholar 

  146. Geiger, H., de Haan, G. & Florian, M.C. The ageing haematopoietic stem cell compartment. Nat. Rev. Immunol. 13, 376–389 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Xing, Z. et al. Increased hematopoietic stem cell mobilization in aged mice. Blood 108, 2190–2197 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Gekas, C. & Graf, T. CD41 expression marks myeloid-biased adult hematopoietic stem cells and increases with age. Blood 121, 4463–4472 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. Singh, K.P. et al. Loss of aryl hydrocarbon receptor promotes gene changes associated with premature hematopoietic stem cell exhaustion and development of a myeloproliferative disorder in aging mice. Stem Cells Dev. 23, 95–106 (2014).

    Article  CAS  PubMed  Google Scholar 

  150. Raffel, G.D. et al. Ott1 (Rbm15) has pleiotropic roles in hematopoietic development. Proc. Natl. Acad. Sci. USA 104, 6001–6006 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Xiao, N. et al. Hematopoietic stem cells lacking Ott1 display aspects associated with aging and are unable to maintain quiescence during proliferative stress. Blood 119, 4898–4907 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Jeannet, R., Cai, Q., Liu, H., Vu, H. & Kuo, Y.H. Alcam regulates long-term hematopoietic stem cell engraftment and self-renewal. Stem Cells 31, 560–571 (2013).

    Article  CAS  PubMed  Google Scholar 

  153. Satoh, Y. et al. The Satb1 protein directs hematopoietic stem cell differentiation toward lymphoid lineages. Immunity 38, 1105–1115 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Geiger, H. & Zheng, Y. Cdc42 and aging of hematopoietic stem cells. Curr. Opin. Hematol. 20, 295–300 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Florian, M.C. et al. A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing. Nature 503, 392–396 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Miyamoto, K. et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1, 101–112 (2007).

    Article  CAS  PubMed  Google Scholar 

  157. Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007).

    Article  CAS  PubMed  Google Scholar 

  158. Jang, Y.Y. & Sharkis, S.J. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 110, 3056–3063 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Norddahl, G.L. et al. Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. Cell Stem Cell 8, 499–510 (2011).

    Article  CAS  PubMed  Google Scholar 

  160. Wang, J. et al. A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage. Cell 148, 1001–1014 (2012).

    Article  CAS  PubMed  Google Scholar 

  161. Mandal, P.K. & Rossi, D.J. DNA-damage–induced differentiation in hematopoietic stem cells. Cell 148, 847–848 (2012).

    Article  CAS  PubMed  Google Scholar 

  162. Janzen, V. et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443, 421–426 (2006).

    Article  CAS  PubMed  Google Scholar 

  163. Köhler, A. et al. Altered cellular dynamics and endosteal location of aged early hematopoietic progenitor cells revealed by time-lapse intravital imaging in long bones. Blood 114, 290–298 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Siclari, V.A. et al. Mesenchymal progenitors residing close to the bone surface are functionally distinct from those in the central bone marrow. Bone 53, 575–586 (2013).

    Article  PubMed  Google Scholar 

  165. Ergen, A.V., Boles, N.C. & Goodell, M.A. Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood 119, 2500–2509 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Villeda, S.A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Owen, M. & Friedenstein, A.J. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found. Symp. 136, 42–60 (1988).

    CAS  PubMed  Google Scholar 

  168. Frenette, P.S., Pinho, S., Lucas, D. & Scheiermann, C. Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine. Annu. Rev. Immunol. 31, 285–316 (2013).

    Article  PubMed  Google Scholar 

  169. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  PubMed  Google Scholar 

  170. Zheng, J. et al. Ex vivo expanded hematopoietic stem cells overcome the MHC barrier in allogeneic transplantation. Cell Stem Cell 9, 119–130 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Csaszar, E. et al. Rapid expansion of human hematopoietic stem cells by automated control of inhibitory feedback signaling. Cell Stem Cell 10, 218–229 (2012).

    Article  CAS  PubMed  Google Scholar 

  172. Holst, J. et al. Substrate elasticity provides mechanical signals for the expansion of hemopoietic stem and progenitor cells. Nat. Biotechnol. 28, 1123–1128 (2010).

    Article  CAS  PubMed  Google Scholar 

  173. Dahlberg, A., Delaney, C. & Bernstein, I.D. Ex vivo expansion of human hematopoietic stem and progenitor cells. Blood 117, 6083–6090 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Sato, T. & Clevers, H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 340, 1190–1194 (2013).

    Article  CAS  PubMed  Google Scholar 

  175. Boehnke, K., Falkowska-Hansen, B., Stark, H.J. & Boukamp, P. Stem cells of the human epidermis and their niche: composition and function in epidermal regeneration and carcinogenesis. Carcinogenesis 33, 1247–1258 (2012).

    Article  CAS  PubMed  Google Scholar 

  176. Myung, P. & Ito, M. Dissecting the bulge in hair regeneration. J. Clin. Invest. 122, 448–454 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Giralt, S. et al. Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations. Biol. Blood Marrow Transplant. 20, 295–308 (2014).

    Article  PubMed  Google Scholar 

  178. Cheuk, D.K. Optimal stem cell source for allogeneic stem cell transplantation for hematological malignancies. World J. Transplant. 3, 99–112 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Hess, D.A. et al. Human progenitor cells rapidly mobilized by AMD3100 repopulate NOD/SCID mice with increased frequency in comparison to cells from the same donor mobilized by granulocyte colony stimulating factor. Biol. Blood Marrow Transplant. 13, 398–411 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Pusic, I. et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol. Blood Marrow Transplant. 14, 1045–1056 (2008).

    Article  CAS  PubMed  Google Scholar 

  181. Ramirez, P. et al. BIO5192, a small molecule inhibitor of VLA-4, mobilizes hematopoietic stem and progenitor cells. Blood 114, 1340–1343 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Miller, C.L., Audet, J. & Eaves, C.J. Ex vivo expansion of human and murine hematopoietic stem cells. Methods Mol. Med. 63, 189–208 (2002).

    PubMed  Google Scholar 

  183. Zhang, C.C. & Lodish, H.F. Murine hematopoietic stem cells change their surface phenotype during ex vivo expansion. Blood 105, 4314–4320 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Jaroscak, J. et al. Augmentation of umbilical cord blood (UCB) transplantation with ex vivo–expanded UCB cells: results of a phase 1 trial using the AastromReplicell System. Blood 101, 5061–5067 (2003).

    Article  CAS  PubMed  Google Scholar 

  185. Boitano, A.E. et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329, 1345–1348 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Ohishi, K., Varnum-Finney, B. & Bernstein, I.D. Delta-1 enhances marrow and thymus repopulating ability of human CD34+CD38− cord blood cells. J. Clin. Invest. 110, 1165–1174 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Delaney, C. et al. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat. Med. 16, 232–236 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Genovese, P. et al. Targeted genome editing in human repopulating haematopoietic stem cells. Nature 510, 235–240 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Isern, J. et al. Self-renewing human bone marrow mesenspheres promote hematopoietic stem cell expansion. Cell Reports 3, 1714–1724 (2013).

    Article  CAS  PubMed  Google Scholar 

  190. Yoshimi, K., Kaneko, T., Voigt, B. & Mashimo, T. Allele-specific genome editing and correction of disease-associated phenotypes in rats using the CRISPR-Cas platform. Nat. Commun. 5, 4240 (2014).

    Article  CAS  PubMed  Google Scholar 

  191. Wei, J. et al. Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell 13, 483–495 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Lane, S.W. et al. Differential niche and Wnt requirements during acute myeloid leukemia progression. Blood 118, 2849–2856 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Colmone, A. et al. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science 322, 1861–1865 (2008).

    Article  CAS  PubMed  Google Scholar 

  194. Schepers, K. et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. Cell Stem Cell 13, 285–299 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Hanoun, M. et al. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell 10.1016/j.stem.2014.06.020 (10 July 2014).

  196. Arranz, L. et al. Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature 10.1038/nature13383 (22 June 2014).

Download references

Author information

Authors and Affiliations

  1. Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA

    Avital Mendelson & Paul S Frenette

  2. The Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Bronx, New York, USA

    Avital Mendelson & Paul S Frenette

  3. Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA

    Paul S Frenette

Authors
  1. Avital Mendelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul S Frenette
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul S Frenette.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mendelson, A., Frenette, P. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med 20, 833–846 (2014). https://doi.org/10.1038/nm.3647

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3647

This article is cited by

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