Li, Juan, Williams, Matthew Joseph, Park, Hyun Jung et al. (19 more authors) (2022) STAT1 is essential for HSC function and maintains MHCIIhi stem cells that resists myeloablation and neoplastic expansion. Blood. ISSN 1528-0020
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.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2022 American Society of Hematology. |
Dates: |
|
Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Physics (York) The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 29 Jul 2022 07:50 |
Last Modified: | 31 Dec 2024 00:13 |
Published Version: | https://doi.org/10.1182/blood.2021014009 |
Status: | Published online |
Refereed: | Yes |
Identification Number: | 10.1182/blood.2021014009 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:189514 |
Downloads
Filename: blood.2021014009.pdf
Description: STAT1 is essential for HSC function and maintains MHCII hi stem cells that resists myeloablation and neoplastic expansion
Licence: CC-BY 2.5
Filename: 99964_1_merged_1656534051.pdf
Description: 99964_1_merged_1656534051