Journal Article

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

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

2014

Overview

Haematopoietic stem cells are direct targets for neurotrophic factors, indicating that haematopoietic stem cells and neurons are regulated by similar signals. RET proto-oncogene aids stem-cell survival Henrique Veiga-Fernandes and colleagues have found that neuronal growth factors are important for survival, expansion and function of haematopoietic stem cells (HSCs). This is achieved though the neurotrophic factor receptor RET, which also provides the surviving cues Bcl2 and Bcl2l1 . Positive modulation of RET signalling drives mouse and human HSC expansion and transplantation, without compromising steady-state haematopoiesis. 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. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Springer Nature
• Subject: 13/106 / 14 / 14/1 / 14/19 / 38/39 / 38/77 / 38/90 / 42/109 / 631/532/1542 / 64/60 / 82/1 / 82/51 / 82/80 / 96/100 / 96/106 / 96/2 / 96/31 / 96/34 / 96/95 / Animals / bcl-X Protein - metabolism / Bone marrow / Cell Survival / Cellular control mechanisms / Cyclic AMP Response Element-Binding Protein - metabolism / Enzyme Activation / Female / Glial cell line-derived neurotrophic factor / Hematopoiesis / Hematopoietic Stem Cell Transplantation / Hematopoietic stem cells / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - metabolism / Humanities and Social Sciences / Humans / letter / Ligands / Male / Mice / Mice, Inbred C57BL / multidisciplinary / Nerve Growth Factors - metabolism / Nervous system / p38 Mitogen-Activated Protein Kinases - metabolism / Phosphorylation / Physiological aspects / Physiology / Proto-Oncogene Proteins c-bcl-2 - metabolism / Proto-Oncogene Proteins c-ret - deficiency / Proto-Oncogene Proteins c-ret - genetics / Proto-Oncogene Proteins c-ret - metabolism / Rodents / Science / Signal Transduction / Stem Cell Niche / Stem cell research / Stem cells / Survival / Transplantation / Transplants & implants