1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada [2] 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.
Nature. 2014 Jun 12;510(7504):268-72. doi: 10.1038/nature13228. Epub 2014 Apr 28.
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 oncogenic 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 repopulation 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 stemness. 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.
血液系统由一群造血干细胞（HSCs）维持，这些细胞由于自我更新的能力而具有长寿性。长寿的一个后果是暴露于应激刺激下，包括活性氧（ROS）、营养波动和 DNA 损伤。应激 HSCs 内发生的损伤必须得到严格控制，以防止功能丧失或致癌突变的克隆持续存在，从而增加白血病发生的风险。尽管维持细胞完整性在整个生命周期中都很重要，但 HSC 池如何实现这一点以及单个 HSC 如何应对应激仍然知之甚少。许多应激源会导致内质网（ER）中错误折叠的蛋白质积累，随后未折叠蛋白反应（UPR）的激活使细胞能够解决应激或启动细胞凋亡。在这里，我们表明，人 HSCs 在 ER 应激后通过 PERK 分支 UPR 的强烈激活易发生细胞凋亡，而密切相关的祖细胞则表现出适应性反应，从而导致其存活。通过过表达伴侣蛋白 ERDJ4（也称为 DNAJB9）增强 ER 蛋白折叠，增加了异种移植实验中 HSC 的再群体能力，将 UPR 与 HSC 功能联系起来。由于 UPR 是不同应激源汇聚的焦点，我们的研究为理解应激信号如何在组织层次结构中协调以及与干性整合提供了一个框架。广义而言，这些发现表明，HSC 池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传播。
