Letter | Published:

The neurotrophic factor receptor RET drives haematopoietic stem cell survival and function

Nature volume 514, pages 98101 (02 October 2014) | Download Citation


Haematopoiesis is a developmental cascade that generates all blood cell lineages in health and disease. This process relies on quiescent haematopoietic stem cells capable of differentiating, self renewing and expanding upon physiological demand1,2. However, the mechanisms that regulate haematopoietic stem cell homeostasis and function remain largely unknown. Here we show that the neurotrophic factor receptor RET (rearranged during transfection) drives haematopoietic stem cell survival, expansion and function. We find that haematopoietic stem cells express RET and that its neurotrophic factor partners are produced in the haematopoietic stem cell environment. Ablation of Ret leads to impaired survival and reduced numbers of haematopoietic stem cells with normal differentiation potential, but loss of cell-autonomous stress response and reconstitution potential. Strikingly, RET signals provide haematopoietic stem cells with critical Bcl2 and Bcl2l1 surviving cues, downstream of p38 mitogen-activated protein (MAP) kinase and cyclic-AMP-response element binding protein (CREB) activation. Accordingly, enforced expression of RET downstream targets, Bcl2 or Bcl2l1, is sufficient to restore the activity of Ret null progenitors in vivo. Activation of RET results in improved haematopoietic stem cell survival, expansion and in vivo transplantation efficiency. Remarkably, human cord-blood progenitor expansion and transplantation is also improved by neurotrophic factors, opening the way for exploration of RET agonists in human haematopoietic stem cell transplantation. Our work shows that neurotrophic factors are novel components of the haematopoietic stem cell microenvironment, revealing that haematopoietic stem cells and neurons are regulated by similar signals.

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  1. 1.

    , & Awakening dormant haematopoietic stem cells. Nature Rev. Immunol. 10, 201–209 (2010)

  2. 2.

    & The bone marrow niche for haematopoietic stem cells. Nature 505, 327–334 (2014)

  3. 3.

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

  4. 4.

    , , & Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008)

  5. 5.

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

  6. 6.

    et al. Tyrosine kinase receptor RET is a key regulator of Peyer’s Patch organogenesis. Nature 446, 547–551 (2007)

  7. 7.

    RET revisited: expanding the oncogenic portfolio. Nature Rev. Cancer 14, 173–186 (2014)

  8. 8.

    et al. RET/GFRα signals are dispensable for thymic T cell development in vivo. PLoS ONE 7, e52949 (2012)

  9. 9.

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

  10. 10.

    , , , & Enhanced purification of fetal liver hematopoietic stem cells using SLAM family receptors. Blood 108, 737–744 (2006)

  11. 11.

    et al. Differential RET signaling pathways drive development of the enteric lymphoid and nervous systems. Sci. Signal. 5, ra55 (2012)

  12. 12.

    et al. Positioning of bone marrow hematopoietic and stromal cells relative to blood flow in vivo: serially reconstituting hematopoietic stem cells reside in distinct nonperfused niches. Blood 116, 375–385 (2010)

  13. 13.

    & Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495, 231–235 (2013)

  14. 14.

    , , , & Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367, 380–383 (1994)

  15. 15.

    et al. Transgenic mice with hematopoietic and lymphoid specific expression of Cre. Eur. J. Immunol. 33, 314–325 (2003)

  16. 16.

    et al. Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal. Cell Stem Cell 1, 338–345 (2007)

  17. 17.

    et al. Molecular evidence for hierarchical transcriptional lineage priming in fetal and adult stem cells and multipotent progenitors. Immunity 26, 407–419 (2007)

  18. 18.

    , , , & Gene expression analysis of purified hematopoietic stem cells and committed progenitors. Blood 102, 94–101 (2003)

  19. 19.

    et al. Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7. J. Exp. Med. 205, 1395–1408 (2008)

  20. 20.

    , , & CREB transcription factor modulates Bcl2 transcription in response to C5a in HL-60-derived neutrophils. Eur. J. Clin. Invest. 36, 353–361 (2006)

  21. 21.

    et al. Activated cAMP response element binding protein is overexpressed in human mesotheliomas and inhibits apoptosis. Am. J. Pathol. 175, 2197–2206 (2009)

  22. 22.

    , , , & Targeted disruption of Bcl-2αβ in mice: occurrence of gray hair, polycystic kidney disease, and lymphocytopenia. Proc. Natl Acad. Sci. USA 91, 3700–3704 (1994)

  23. 23.

    et al. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 267, 1506–1510 (1995)

  24. 24.

    et al. GFRα1 is an essential receptor component for GDNF in the developing nervous system and kidney. Neuron 21, 53–62 (1998)

  25. 25.

    et al. GFR α3, a component of the artemin receptor, is required for migration and survival of the superior cervical ganglion. Neuron 23, 725–736 (1999)

  26. 26.

    et al. Retarded growth and deficits in the enteric and parasympathetic nervous system in mice lacking GFR α2, a functional neurturin receptor. Neuron 22, 243–252 (1999)

  27. 27.

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

  28. 28.

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

  29. 29.

    et al. Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling. Nature Immunol. 8, 1123–1131 (2007)

  30. 30.

    et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992)

  31. 31.

    & Neural precursor death is central to the pathogenesis of intestinal aganglionosis in Ret hypomorphic mice. J. Neurosci. 30, 5211–5218 (2010)

  32. 32.

    et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502, 637–643 (2014)

  33. 33.

    et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014)

  34. 34.

    et al. CD8 single-cell gene coexpression reveals three different effector types present at distinct phases of the immune response. J. Exp. Med. 204, 1193–1205 (2007)

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We thank I. Monteiro Grillo and the radiotherapy service at Hospital de Santa Maria; H. Ferreira and the service of obstetrics, gynaecology and reproductive medicine at the Hospital of Santa Maria; the Instituto de Medicina Molecular animal facility, flow cytometry unit, bioimaging unit and histology unit for technical assistance. We also thank all members of H.V.-F. laboratory for discussion. D.F.-P., S.A.-M., R.G.D. and A.R.M.A. were supported by scholarships from Fundação para a Ciência e Tecnologia, Portugal. H.V.-F. was supported by Fundação para a Ciência e Tecnologia (PTDC/SAU-MII/104931/2008), Portugal, the European Molecular Biology Organisation (Project 1648), European Research Council (Project 207057) and National Blood Foundation, USA.

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Author notes

    • Diogo Fonseca-Pereira
    •  & Sílvia Arroz-Madeira

    These authors contributed equally to this work.


  1. Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Avenida Professor Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal

    • Diogo Fonseca-Pereira
    • , Sílvia Arroz-Madeira
    • , Mariana Rodrigues-Campos
    • , Inês A. M. Barbosa
    • , Rita G. Domingues
    • , Teresa Bento
    • , Afonso R. M. Almeida
    • , Hélder Ribeiro
    •  & Henrique Veiga-Fernandes
  2. Division of Molecular Immunology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK

    • Alexandre J. Potocnik
  3. Institute of Immunology and Infection Research, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK

    • Alexandre J. Potocnik
  4. Laboratory for Neuronal Differentiation and Regeneration, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan

    • Hideki Enomoto
  5. Graduate School of Medicine, Kobe University7-5-1 Kusunoki-cho, Chuo-ku, Kobe City, Hyogo 650-0017, Japan

    • Hideki Enomoto


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D.F.-P., S.A.-M., M.R.-C., I.B., R.G.D., T.B., A.R.M.A. and H.R. did experiments and data analysis; H.E. generated RetBCLxL mice; D.F.-P., S.A.-M., A.P. and H.V.-F. designed in vivo and ex vivo experiments; D.F.-P. and H.V.-F. wrote the manuscript and H.V.-F. directed the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Henrique Veiga-Fernandes.

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