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首页> 外文期刊>Nature >The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress
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The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress

机译：应激期间未折叠的蛋白质反应决定着造血干细胞池的完整性

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摘要

The blood system is sustained by a pool of haematopoietic stem cells (HSCs) that are long-lived due to their capacity for self-renewal. A consequence of longevity is exposure to stress stimuli including reactive oxygen species (ROS), nutrient fluctuation and DNA damage. Damage that occurs within stressed HSCs must be tightly controlled to prevent either loss of function or the clonal persistence of onco-genic mutations that increase the risk of leukaemogenesis. Despite the importance of maintaining cell integrity throughout life, how the HSC pool achieves this and how individual HSCs respond to stress remain poorly understood. Many sources of stress cause misfolded protein accumulation in the endoplasmic reticulum (ER), and subsequent activation of the unfolded protein response (UPR) enables the cell to either resolve stress or initiate apoptosis. Here we show that human HSCs are predisposed to apoptosis through strong activation of the PERK branch of the UPR after ER stress, whereas closely related progenitors exhibit an adaptive response leading to their survival. Enhanced ER protein folding by overexpression of the co-chaperone ERDJ4 (also called DNAJB9) increases HSC repopula-tion capacity in xenograft assays, linking the UPR to HSC function. Because the UPR is a focal point where different sources of stress converge, our study provides a framework for understanding how stress signalling is coordinated within tissue hierarchies and integrated with sternness. Broadly, these findings reveal that the HSC pool maintains clonal integrity by clearance of individual HSCs after stress to prevent propagation of damaged stem cells.
机译：血液系统由造血干细胞（HSC）库维持，这些造血干细胞由于具有自我更新的能力而寿命长。长寿的结果是暴露于应力刺激下，包括活性氧（ROS），营养物质波动和DNA损伤。必须严格控制在受压的HSC内发生的损害，以防止功能丧失或致癌基因突变的克隆持续存在，从而增加白细胞生成的风险。尽管在整个生命中维持细胞完整性很重要，但HSC池如何实现这一目标以及单个HSC如何应对压力仍然知之甚少。许多压力源会导致内质网（ER）中蛋白质积累的折叠错误，随后展开的蛋白质反应（UPR）的激活使细胞能够缓解应力或启动细胞凋亡。在这里，我们显示人类HSCs通过内质网应激后UPR的PERK分支的强烈激活而易于凋亡，而密切相关的祖细胞则显示出导致其存活的适应性反应。通过伴侣蛋白ERDJ4（也称为DNAJB9）的过表达增强的ER蛋白折叠，在异种移植测定中增加了HSC的再增殖能力，从而将UPR与HSC功能联系起来。由于普遍定期审议是不同压力源汇聚的焦点，因此我们的研究提供了一个框架，用于了解应力信号在组织层次结构中如何进行协调并与严峻性相结合。广泛地，这些发现揭示了HSC库通过在应激后清除单个HSC来维持克隆完整性，以防止受损干细胞的繁殖。

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  • 来源
    《Nature》 |2014年第7504期|268-272|共5页
  • 作者

    Peter van Galen; Antonija Kreso; Nathan Mbong; David G. Kent; Timothy Fitzmaurice; Joseph E. Chambers; Stephanie Xie; Elisa Laurenti; Karin Hermans; Kolja Eppert; Stefan J. Marciniak; Jane C. Goodall; Anthony R. Green; Bradly G. Wouters; Erno Wienholds; John E. Dick;

  • 作者单位

    Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada,Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

    Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada,Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

    Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada,Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

    Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute and Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK;

    Department of Medicine, School of Clinical Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge CB2 0QQ, UK;

    Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute and Department of Medicine, University of Cambridge, Cambridge CB2 0XY, UK;

    Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada,Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

    Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada,Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

    Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada,Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

    Department of Pediatrics, McGill University and the Research Institute of the McGill University Health Centre, Westmount, Quebec H3Z 2Z3, Canada;

    Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute and Department of Medicine, University of Cambridge, Cambridge CB2 0XY, UK;

    Department of Medicine, School of Clinical Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge CB2 0QQ, UK;

    Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute and Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK;

    Departments of Radiation Oncology and Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada;

    Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada,Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

    Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada,Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

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