Publication Date:
2014-04-30
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉van Galen, Peter -- Kreso, Antonija -- Mbong, Nathan -- Kent, David G -- Fitzmaurice, Timothy -- Chambers, Joseph E -- Xie, Stephanie -- Laurenti, Elisa -- Hermans, Karin -- Eppert, Kolja -- Marciniak, Stefan J -- Goodall, Jane C -- Green, Anthony R -- Wouters, Bradly G -- Wienholds, Erno -- Dick, John E -- 100140/Wellcome Trust/United Kingdom -- 19639/Arthritis Research UK/United Kingdom -- 201592/Canadian Institutes of Health Research/Canada -- G1002610/Medical Research Council/United Kingdom -- Arthritis Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2014 Jun 12;510(7504):268-72. doi: 10.1038/nature13228. Epub 2014 Apr 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; 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. ; Department of Pediatrics, McGill University and the Research Institute of the McGill University Health Centre, Westmount, Quebec H3Z 2Z3, Canada. ; Departments of Radiation Oncology and Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24776803" target="_blank"〉PubMed〈/a〉
Keywords:
Activating Transcription Factor 4/metabolism
;
Animals
;
Apoptosis/drug effects
;
*Endoplasmic Reticulum Stress/drug effects
;
Eukaryotic Initiation Factor-2/metabolism
;
HSP40 Heat-Shock Proteins/metabolism
;
Hematopoietic Stem Cells/*cytology/drug effects
;
Heterografts
;
Humans
;
Male
;
Membrane Proteins/metabolism
;
Mice
;
Molecular Chaperones/metabolism
;
Protein Folding
;
Protein Phosphatase 1/metabolism
;
Signal Transduction
;
Transcription Factor CHOP/metabolism
;
Tunicamycin/pharmacology
;
Unfolded Protein Response/drug effects/*physiology
;
eIF-2 Kinase/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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