STAT1 is essential for HSC function and maintains MHCIIhi stem cells that resists myeloablation and neoplastic expansion.
Authors
Li, Juan
Williams, Matthew Joseph
Park, Hyun Jung
Prins, Daniel Prins
Johnson, Carys
Sham, Kendig
Wantoch, Michelle
Watcham, Sam
Kinston, Sarah Jane
Pask, Dean C
Hamilton, Tina L
Sneade, Rachel
Waller, Amie Karen
Publication Date
2022-06-29Journal Title
Blood
ISSN
0006-4971
Publisher
American Society of Hematology
Pages
blood.2021014009
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Li, J., Williams, M. J., Park, H. J., Bastos, H. P., Wang, X., Prins, D. P., Wilson, N., et al. (2022). STAT1 is essential for HSC function and maintains MHCIIhi stem cells that resists myeloablation and neoplastic expansion.. Blood, blood.2021014009. https://doi.org/10.1182/blood.2021014009
Abstract
Adult 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 which protect HSCs including control of quiescence. Our results also reveal STAT1-dependent functional HSC heterogeneity. A previously unrecognized subset of homeostatic HSCs with elevated MHCII expression (MHCIIhi) displayed molecular features of reduced cycling and apoptosis, and was refractory to 5-FU 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.
Sponsorship
Wellcome Trust (203151/Z/16/Z)
Wellcome Trust (203151/A/16/Z)
Identifiers
External DOI: https://doi.org/10.1182/blood.2021014009
This record's URL: https://www.repository.cam.ac.uk/handle/1810/338757
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