期刊
NATURE
卷 514, 期 7520, 页码 98-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13498
关键词
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资金
- Fundacao para a Ciencia e Tecnologia, Portugal
- Fundacao para a Ciencia e Tecnologia, Portugal [PTDC/SAU-MII/104931/2008]
- European Molecular Biology Organisation [1648]
- European Research Council [207057]
- National Blood Foundation, USA
- Grants-in-Aid for Scientific Research [22122005] Funding Source: KAKEN
- Medical Research Council [MC_U117565359] Funding Source: researchfish
- MRC [MC_U117565359] Funding Source: UKRI
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-MII/104931/2008] Funding Source: FCT
- European Research Council (ERC) [207057] Funding Source: European Research Council (ERC)
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(1,2). 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. Ourwork shows that neurotrophic factors are novel components of the haematopoietic stem cell microenvironment, revealing that
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