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STAT1 is essential for HSC function and maintains MHCIIhi stem cells that resist myeloablation and neoplastic expansion.

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cam.depositDate2022-07-04
cam.issuedOnline2022-06-29
dc.contributor.authorLi, Juan
dc.contributor.authorWilliams, Matthew J
dc.contributor.authorPark, Hyun Jung
dc.contributor.authorBastos, Hugo P
dc.contributor.authorWang, Xiaonan
dc.contributor.authorPrins, Daniel
dc.contributor.authorWilson, Nicola K
dc.contributor.authorJohnson, Carys
dc.contributor.authorSham, Kendig
dc.contributor.authorWantoch, Michelle
dc.contributor.authorWatcham, Sam
dc.contributor.authorKinston, Sarah J
dc.contributor.authorPask, Dean C
dc.contributor.authorHamilton, Tina L
dc.contributor.authorSneade, Rachel
dc.contributor.authorWaller, Amie K
dc.contributor.authorGhevaert, Cedric
dc.contributor.authorVassiliou, George S
dc.contributor.authorLaurenti, Elisa
dc.contributor.authorKent, David G
dc.contributor.authorGöttgens, Berthold
dc.contributor.authorGreen, Anthony R
dc.contributor.orcidBastos, Hugo P [0000-0002-8072-4070]
dc.contributor.orcidWang, Xiaonan [0000-0003-3759-778X]
dc.contributor.orcidWilson, Nicola K [0000-0003-0865-7333]
dc.contributor.orcidVassiliou, George S [0000-0003-4337-8022]
dc.contributor.orcidLaurenti, Elisa [0000-0002-9917-9092]
dc.contributor.orcidKent, David G [0000-0001-7871-8811]
dc.date.accessioned2022-07-04T23:30:49Z
dc.date.available2022-07-04T23:30:49Z
dc.date.issued2022-10-06
dc.date.updated2022-07-04T12:00:40Z
dc.description.abstractAdult hematopoietic stem cells (HSCs) are predominantly quiescent and can be activated in response to acute stress such as infection or cytotoxic insults. STAT1 is a pivotal downstream mediator of interferon (IFN) signaling and is required for IFN-induced HSC proliferation, but little is known about the role of STAT1 in regulating homeostatic hematopoietic stem/progenitor cells (HSPCs). Here, we show that loss of STAT1 altered the steady state HSPC landscape, impaired HSC function in transplantation assays, delayed blood cell regeneration following myeloablation, and disrupted molecular programs that protect HSCs, including control of quiescence. Our results also reveal STAT1-dependent functional HSC heterogeneity. A previously unrecognized subset of homeostatic HSCs with elevated major histocompatibility complex class II (MHCII) expression (MHCIIhi) displayed molecular features of reduced cycling and apoptosis and was refractory to 5-fluorouracil-induced myeloablation. Conversely, MHCIIlo HSCs displayed increased megakaryocytic potential and were preferentially expanded in CALR mutant mice with thrombocytosis. Similar to mice, high MHCII expression is a feature of human HSCs residing in a deeper quiescent state. Our results therefore position STAT1 at the interface of stem cell heterogeneity and the interplay between stem cells and the adaptive immune system, areas of broad interest in the wider stem cell field.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.86167
dc.identifier.eissn1528-0020
dc.identifier.issn0006-4971
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338757
dc.language.isoeng
dc.publisherAmerican Society of Hematology
dc.publisher.departmentDepartment of Haematology
dc.publisher.urlhttp://dx.doi.org/10.1182/blood.2021014009
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnimals
dc.subjectCell Proliferation
dc.subjectFluorouracil
dc.subjectHematopoietic Stem Cells
dc.subjectHumans
dc.subjectInterferons
dc.subjectMegakaryocytes
dc.subjectMice
dc.subjectSTAT1 Transcription Factor
dc.titleSTAT1 is essential for HSC function and maintains MHCIIhi stem cells that resist myeloablation and neoplastic expansion.
dc.typeArticle
dcterms.dateAccepted2022-04-21
prism.publicationDate2022
prism.publicationNameBlood
prism.startingPageblood.2021014009
pubs.funder-project-idWellcome Trust (203151/Z/16/Z)
pubs.funder-project-idWellcome Trust (203151/A/16/Z)
pubs.funder-project-idMedical Research Council (MR/M008975/1)
pubs.funder-project-idMedical Research Council (1942750)
pubs.funder-project-idBloodwise (18002)
pubs.funder-project-idMedical Research Council (MC_PC_17230)
pubs.funder-project-idWellcome Trust (104710/Z/14/Z)
pubs.funder-project-idMedical Research Council (MR/V005413/1)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
pubs.licence-identifierapollo-deposit-licence-2-1
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1182/blood.2021014009

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