The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress.
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.
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.
Peter
P
van Galen
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.
Antonija
A
Kreso
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.
Nathan
N
Mbong
Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute and Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
David G
DG
Kent
Department of Medicine, School of Clinical Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge CB2 0QQ, UK.
Timothy
T
Fitzmaurice
Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute and Department of Medicine, University of Cambridge, Cambridge CB2 0XY, UK.
Joseph E
JE
Chambers
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.
Stephanie
S
Xie
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.
Elisa
E
Laurenti
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.
Karin
K
Hermans
Department of Pediatrics, McGill University and the Research Institute of the McGill University Health Centre, Westmount, Québec H3Z 2Z3, Canada.
Kolja
K
Eppert
Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute and Department of Medicine, University of Cambridge, Cambridge CB2 0XY, UK.
Stefan J
SJ
Marciniak
Department of Medicine, School of Clinical Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge CB2 0QQ, UK.
Jane C
JC
Goodall
Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute and Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
Anthony R
AR
Green
Departments of Radiation Oncology and Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
Bradly G
BG
Wouters
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.
Erno
E
Wienholds
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.
John E
JE
Dick
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism; D017510:Protein Folding; D054645:Protein Phosphatase 1 / Q000378:metabolism; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology*; D019892:eIF-2 Kinase / Q000378:metabolism
C497109:ATF4 protein, human; C497249:DDIT3 protein, human; C478021:DNAJB9 protein, human; D015852:Eukaryotic Initiation Factor-2; D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1