TY - JOUR
T1 - M-CSF instructs myeloid lineage fate in single haematopoietic stem cells
AU - Mossadegh-Keller, Noushine
AU - Sarrazin, Sandrine
AU - Kandalla, Prashanth K.
AU - Espinosa, Leon
AU - Richard Stanley, E.
AU - Nutt, Stephen L.
AU - Moore, Jordan
AU - Sieweke, Michael H.
N1 - Funding Information:
Acknowledgements We acknowledge grants from the ‘Association pour la recherche sur le Cancer’ (3422) and the ‘Agence nationale de la Recherche’ (BLAN07-1_205752). We thank P. Kastner and S. Chan for PU.1-GFP reporter mice; T. P. VuManh and J. Maurizio for bioinformatics; M. Barad, A. Zouine and M.-L. Thibult for flow cytometry support; L. Razafindramanana for animal handling; and J. Favret, P. Perrin and L. Chasson for tissue sectioning. E.R.S. is supported by NIH grant CA 32551. S.L.N. is an Australian Research Council Future Fellow and received Victorian State Government Operational and Australian Government NHMRC Independent Research Institute Infrastructure Support. M.H.S. is a ‘Fondation pour la Recherche Médicale’ (DEQ20071210559; DEQ20110421320) and INSERM-Helmholtz group leader.
PY - 2013
Y1 - 2013
N2 - Under stress conditions such as infection or inflammation the body rapidly needs to generate new blood cells that are adapted to the challenge. Haematopoietic cytokines are known to increase output of specific mature cells by affecting survival, expansion and differentiation of lineage-committed progenitors, but it has been debated whether long-term haematopoietic stem cells (HSCs) are susceptible to direct lineage-specifying effects of cytokines. Although genetic changes in transcription factor balance can sensitize HSCs to cytokine instruction, the initiation of HSC commitment is generally thought to be triggered by stochastic fluctuation in cell-intrinsic regulators such as lineage-specific transcription factors, leaving cytokines to ensure survival and proliferation of the progeny cells. Here we show that macrophage colony-stimulating factor (M-CSF, also called CSF1), a myeloid cytokine released during infection and inflammation, can directly induce the myeloid master regulator PU.1 and instruct myeloid cell-fate change in mouse HSCs, independently of selective survival or proliferation. Video imaging and single-cell gene expression analysis revealed that stimulation of highly purified HSCs with M-CSF in culture resulted in activation of the PU.1 promoter and an increased number of PU.1 + cells with myeloid gene signature and differentiation potential. In vivo, high systemic levels of M-CSF directly stimulated M-CSF-receptor-dependent activation of endogenous PU.1 protein in single HSCs and induced a PU.1-dependent myeloid differentiation preference. Our data demonstrate that lineage-specific cytokines can act directly on HSCs in vitro and in vivo to instruct a change of cell identity. This fundamentally changes the current view of how HSCs respond to environmental challenge and implicates stress-induced cytokines as direct instructors of HSC fate.
AB - Under stress conditions such as infection or inflammation the body rapidly needs to generate new blood cells that are adapted to the challenge. Haematopoietic cytokines are known to increase output of specific mature cells by affecting survival, expansion and differentiation of lineage-committed progenitors, but it has been debated whether long-term haematopoietic stem cells (HSCs) are susceptible to direct lineage-specifying effects of cytokines. Although genetic changes in transcription factor balance can sensitize HSCs to cytokine instruction, the initiation of HSC commitment is generally thought to be triggered by stochastic fluctuation in cell-intrinsic regulators such as lineage-specific transcription factors, leaving cytokines to ensure survival and proliferation of the progeny cells. Here we show that macrophage colony-stimulating factor (M-CSF, also called CSF1), a myeloid cytokine released during infection and inflammation, can directly induce the myeloid master regulator PU.1 and instruct myeloid cell-fate change in mouse HSCs, independently of selective survival or proliferation. Video imaging and single-cell gene expression analysis revealed that stimulation of highly purified HSCs with M-CSF in culture resulted in activation of the PU.1 promoter and an increased number of PU.1 + cells with myeloid gene signature and differentiation potential. In vivo, high systemic levels of M-CSF directly stimulated M-CSF-receptor-dependent activation of endogenous PU.1 protein in single HSCs and induced a PU.1-dependent myeloid differentiation preference. Our data demonstrate that lineage-specific cytokines can act directly on HSCs in vitro and in vivo to instruct a change of cell identity. This fundamentally changes the current view of how HSCs respond to environmental challenge and implicates stress-induced cytokines as direct instructors of HSC fate.
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U2 - 10.1038/nature12026
DO - 10.1038/nature12026
M3 - Article
C2 - 23575636
AN - SCOPUS:84877787762
SN - 0028-0836
VL - 497
SP - 239
EP - 243
JO - Nature
JF - Nature
IS - 7448
ER -