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M-CSF instructs myeloid lineage fate in singlehaematopoietic stem cells

机译：M-CSF指导单系造血干细胞的骨髓谱系命运

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摘要

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~(4-7), 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.
机译：在感染或炎症等应激条件下，人体迅速需要生成新的血细胞以适应挑战。〜*已知造血细胞因子可通过影响血统承诺祖细胞的存活，扩增和分化来增加特定成熟细胞的产量〜 （1'2），但长期的造血干细胞（HSC）是否易受细胞因子直接谱系确定作用的影响尚有争议。尽管转录因子平衡的遗传变化可使HSC对细胞因子指令3敏感，但通常认为HSC承诺的启动是由细胞内调控因子（如谱系特异性转录因子〜（4-7））的随机波动触发的，因此细胞因子，以确保子代细胞的存活和增殖〜（8,9）。在这里，我们显示巨噬细胞集落刺激因子（M-CSF，也称为CSF1）是在感染和炎症过程中释放的髓样细胞因子，可以直接诱导髓样主调节因子PU.1并指示小鼠HSC中髓样细胞命运的变化。选择生存或增殖。视频成像和单细胞基因表达分析表明，在培养物中用M-CSF刺激高度纯化的HSC会激活PU.1启动子，并增加具有髓样基因特征和分化潜能的PU.1〜+细胞。在体内，高系统水平的M-CSF直接刺激单个HSC中内源性PU.1蛋白的M-CSF受体依赖性激活，并诱导PU.1依赖性骨髓分化。我们的数据表明，谱系特异性细胞因子可以在体外和体内直接作用于HSC，以指导细胞身份的改变。这从根本上改变了目前关于HSC如何应对环境挑战的观点，并暗示应激诱导的细胞因子是HSC命运的直接指导者。

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  • 来源
    《Nature》 |2013年第7448期|239-243|共5页
  • 作者

    Noushine Mossadegh-Keller; Sandrine Sarrazin; Prashanth K. Kandalla; Leon Espinosa; E. Richard Stanley; Stephen L. Nutt; Jordan Moore; Michael H. Sieweke;

  • 作者单位

    Centre d'lmmunologie de Marseille-Luminy, Aix-Marseille Universite, UM2, Campus de Luminy, Case 906,13288 Marseille Cedex 09, France,lnstitut National de la Sante et de la Recherche Medicale,Ul 104, Campus de Luminy, Case 906,13288 Marseille Cedex 09, France,Centre National de la Recherche Scientifique, UMR7280, Campus de Luminy, Case 906,13288 Marseille Cedex 09, France;

    Centre d'lmmunologie de Marseille-Luminy, Aix-Marseille Universite, UM2, Campus de Luminy, Case 906,13288 Marseille Cedex 09, France,lnstitut National de la Sante et de la Recherche Medicale,Ul 104, Campus de Luminy, Case 906,13288 Marseille Cedex 09, France,Centre National de la Recherche Scientifique, UMR7280, Campus de Luminy, Case 906,13288 Marseille Cedex 09, France;

    Centre d'lmmunologie de Marseille-Luminy, Aix-Marseille Universite, UM2, Campus de Luminy, Case 906,13288 Marseille Cedex 09, France,lnstitut National de la Sante et de la Recherche Medicale,Ul 104, Campus de Luminy, Case 906,13288 Marseille Cedex 09, France,Centre National de la Recherche Scientifique, UMR7280, Campus de Luminy, Case 906,13288 Marseille Cedex 09, France;

    Laboratoire de Chimie Bacterienne, Centre National de la Recherche Scientifique, UMR 7283,31 Chemin Joseph Aiguier, 13009 Marseille, France;

    Departmentof Developmental and Molecular Biology,Albert Einstein College of Medicine, Bronx, New York 10461, USA;

    Walterand Eliza Hall Institute, 1G Royal Parade, Parkville, Victoria 3052, Australia;

    Fluidigm Corporation, South San Francisco, California 94080, USA;

    Centre d'lmmunologie de Marseille-Luminy, Aix-Marseille Universite, UM2, Campus de Luminy, Case 906,13288 Marseille Cedex 09, France,lnstitut National de la Sante et de la Recherche Medicale,Ul 104, Campus de Luminy, Case 906,13288 Marseille Cedex 09, France,Centre National de la Recherche Scientifique, UMR7280, Campus de Luminy, Case 906,13288 Marseille Cedex 09, France,Max-Delbruck-Centrum fur Molekulare Medizin, Robert-R6ssle-Str. 10,13125 Berlin, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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