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

Diogo Fonseca-Pereira, Sílvia Arroz-Madeira, Mariana Rodrigues-Campos, Inês A. M. Barbosa, Rita G. Domingues, Teresa Bento, Afonso R. M. Almeida, Hélder Ribeiro, A.J. Potocnik, Hideki Enomoto, Henrique Veiga-Fernandes

Research output: Contribution to journalLetterpeer-review

Abstract

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 demand. 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.

Original languageEnglish
Pages (from-to)98-101
Number of pages4
JournalNature
Volume514
Issue number7520
Early online date27 Jul 2014
DOIs
Publication statusPublished - 2 Oct 2014

Keywords

  • BCL2L1 protein
  • Bcl2l1 protein
  • cyclic AMP responsive element binding protein
  • mitogen activated protein kinase p38
  • nerve growth factor
  • protein bcl 2
  • protein bcl x
  • protein ret
  • RET protein
  • inbred C57BL
  • animal
  • article
  • C57BL mouse
  • cell survival
  • cytology
  • enzyme activation
  • female
  • genetics
  • hematopoiesis
  • hematopoietic stem cell
  • hematopoietic stem cell transplantation
  • human
  • male
  • metabolism
  • mouse
  • signal transduction
  • stem cell niche
  • animals
  • bcl-X Protein
  • cyclic AMP response element-Binding Protein
  • hematopoietic stem cells
  • humans
  • mice
  • nerve growth factors
  • p38 Mitogen-Activated Protein Kinases
  • proto-oncogene proteins c-bcl-2/metabolism
  • proto-oncogene proteins c-ret

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