期刊
NATURE
卷 510, 期 7504, 页码 268-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13228
关键词
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资金
- Canadian Institutes for Health Research
- Canadian Cancer Society
- Terry Fox Foundation
- Genome Canada through the Ontario Genomics Institute
- Ontario Institute for Cancer Research
- province of Ontario
- Canada Research Chair
- Ontario Ministry of Health and Long Term Care (OMOHLTC)
- Leukemia and Lymphoma Research
- Cancer Research UK
- Kay Kendall Leukaemia Fund
- NIHR Cambridge Biomedical Research Centre
- Cambridge Experimental Cancer Medicine Centre
- Leukemia & Lymphoma Society of America
- Arthritis Research UK
- Medical Research Council (UK)
- Terry Fox New Frontiers Research Program [PPG09-020005]
- Canadian Institute for Health Research (CIHR) [201592]
- Medical Research Council [G1001765, G0601840, G1002610] Funding Source: researchfish
- Versus Arthritis [19639] Funding Source: researchfish
- MRC [G1001765, G1002610, G0601840] Funding Source: UKRI
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(1,2). 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(3,4). 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(5,6). 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 cochaperone 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.
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