The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress.
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Authors
van Galen, Peter
Kreso, Antonija
Mbong, Nathan
Xie, Stephanie
Hermans, Karin
Eppert, Kolja
Wouters, Bradly G
Wienholds, Erno
Dick, John E
Publication Date
2014-06-12Journal Title
Nature
ISSN
0028-0836
Publisher
Springer Science and Business Media LLC
Volume
510
Issue
7504
Pages
268-272
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
van Galen, P., Kreso, A., Mbong, N., Kent, D., Fitzmaurice, T., Chambers, J., Xie, S., et al. (2014). The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress.. Nature, 510 (7504), 268-272. https://doi.org/10.1038/nature13228
Abstract
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.
Keywords
Hematopoietic Stem Cells, Animals, Humans, Mice, eIF-2 Kinase, Membrane Proteins, Molecular Chaperones, Eukaryotic Initiation Factor-2, Tunicamycin, Signal Transduction, Apoptosis, Protein Folding, Male, HSP40 Heat-Shock Proteins, Activating Transcription Factor 4, Transcription Factor CHOP, Protein Phosphatase 1, Unfolded Protein Response, Endoplasmic Reticulum Stress, Heterografts
Sponsorship
Arthritis Research Uk (None)
Medical Research Council (G1002610)
Medical Research Council (G1001765)
Medical Research Council (G0601840)
Wellcome Trust (100140/Z/12/Z)
Identifiers
External DOI: https://doi.org/10.1038/nature13228
This record's URL: https://www.repository.cam.ac.uk/handle/1810/275608
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