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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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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Nature Immunology (2017)