M-CSF instructs myeloid lineage fate in single haematopoietic stem cells

• Published in: Nature (London) Vol. 497; no. 7448; pp. 239 - 243
• Main Authors: Mossadegh-Keller, Noushine, Sarrazin, Sandrine, Kandalla, Prashanth K., Espinosa, Leon, Stanley, E. Richard, Nutt, Stephen L., Moore, Jordan, Sieweke, Michael H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.05.2013; Nature Publishing Group
• Subjects: 631/136/532/1542; 631/250/127; 631/532/1542; Animals; Cell Differentiation - drug effects; Cell division; Cell Lineage - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cytokines; Gene expression; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Humanities and Social Sciences; Infections; letter; Macrophage colony stimulating factor; Macrophage Colony-Stimulating Factor - pharmacology; Mice; Mice, Inbred C57BL; Microscopy; multidisciplinary; Myeloid Cells - cytology; Myeloid Cells - drug effects; Promoter Regions, Genetic - genetics; Properties; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Science; Single-Cell Analysis; Stem cells; Trans-Activators - biosynthesis; Trans-Activators - genetics; Trans-Activators - metabolism; United Kingdom
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12026

M-CSF, a myeloid cytokine released during infection and inflammation, instructs myeloid lineage fate in single haematopoietic stem cells by directly inducing PU.1, a known myeloid lineage master regulator; this shows that specific cytokines can act directly on haematopoietic stem cells to instruct a change of cell identity. Cytokine-directed stem-cell differentiation Lineage-specific cytokines such as macrophage colony-stimulating factor (M-CSF), which is released during infection and inflammation, can potently increase the production of mature cells from lineage-committed progenitors, but whether they influence differentiation decisions of haematopoietic stem cells directly has been a matter of debate. Now Michael Sieweke and colleagues report that M-CSF instructs myeloid lineage fate by directly inducing PU.1, a known myeloid lineage master regulator. Through this mechanism cytokines released during stress may direct stem-cell differentiation towards cells tailored to cope with that specific stress. This might also provide opportunities for the manipulation of stem-cell fate under pathological or transplantation conditions. 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 1 , 2 , 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 3 , the initiation of HSC commitment is generally thought to be triggered by stochastic fluctuation in cell-intrinsic regulators such as lineage-specific transcription factors 4 , 5 , 6 , 7 , leaving cytokines to ensure survival and proliferation of the progeny cells 8 , 9 . 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.