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dc.contributor.authorvan Galen, Peter
dc.contributor.authorKreso, Antonija
dc.contributor.authorMbong, Nathan
dc.contributor.authorKent, David G
dc.contributor.authorFitzmaurice, Timothy
dc.contributor.authorChambers, Joseph E
dc.contributor.authorXie, Stephanie
dc.contributor.authorLaurenti, Elisa
dc.contributor.authorHermans, Karin
dc.contributor.authorEppert, Kolja
dc.contributor.authorMarciniak, Stefan J
dc.contributor.authorGoodall, Jane C
dc.contributor.authorGreen, Anthony R
dc.contributor.authorWouters, Bradly G
dc.contributor.authorWienholds, Erno
dc.contributor.authorDick, John E
dc.date.accessioned2018-05-08T11:47:36Z
dc.date.available2018-05-08T11:47:36Z
dc.date.issued2014-06-12
dc.identifier.issn0028-0836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/275608
dc.description.abstractThe 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.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.subjectHematopoietic Stem Cells
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjecteIF-2 Kinase
dc.subjectMembrane Proteins
dc.subjectMolecular Chaperones
dc.subjectEukaryotic Initiation Factor-2
dc.subjectTunicamycin
dc.subjectSignal Transduction
dc.subjectApoptosis
dc.subjectProtein Folding
dc.subjectMale
dc.subjectHSP40 Heat-Shock Proteins
dc.subjectActivating Transcription Factor 4
dc.subjectTranscription Factor CHOP
dc.subjectProtein Phosphatase 1
dc.subjectUnfolded Protein Response
dc.subjectEndoplasmic Reticulum Stress
dc.subjectHeterografts
dc.titleThe unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress.
dc.typeArticle
prism.endingPage272
prism.issueIdentifier7504
prism.publicationDate2014
prism.publicationNameNature
prism.startingPage268
prism.volume510
dc.identifier.doi10.17863/CAM.22862
dcterms.dateAccepted2014-03-05
rioxxterms.versionofrecord10.1038/nature13228
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2014-06
dc.contributor.orcidKent, David [0000-0001-7871-8811]
dc.contributor.orcidFitzmaurice, Tim [0000-0003-1403-2495]
dc.contributor.orcidChambers, Joseph [0000-0003-4675-0053]
dc.contributor.orcidLaurenti, Elisa [0000-0002-9917-9092]
dc.contributor.orcidMarciniak, Stefan [0000-0001-8472-7183]
dc.contributor.orcidGoodall, Jane [0000-0002-3761-161X]
dc.contributor.orcidGreen, Tony [0000-0002-9795-0218]
dc.identifier.eissn1476-4687
rioxxterms.typeJournal Article/Review
pubs.funder-project-idArthritis Research Uk (None)
pubs.funder-project-idMedical Research Council (G1002610)
pubs.funder-project-idMedical Research Council (G1001765)
pubs.funder-project-idMedical Research Council (G0601840)
pubs.funder-project-idWellcome Trust (100140/Z/12/Z)
cam.issuedOnline2014-04-28
rioxxterms.freetoread.startdate2018-04-28


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