PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

Open access
Date
2021-06-07Type
- Journal Article
Citations
Cited 19 times in
Web of Science
Cited 23 times in
Scopus
ETH Bibliography
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Abstract
Hematopoietic stem cells (HSCs) are capable of entering the cell cycle to replenish the blood system in response to inflammatory cues; however, excessive proliferation in response to chronic inflammation can lead to either HSC attrition or expansion. The mechanism(s) that limit HSC proliferation and expansion triggered by inflammatory signals are poorly defined. Here, we show that long-term HSCs (HSCLT) rapidly repress protein synthesis and cell cycle genes following treatment with the proinflammatory cytokine interleukin (IL)-1. This gene program is associated with activation of the transcription factor PU.1 and direct PU.1 binding at repressed target genes. Notably, PU.1 is required to repress cell cycle and protein synthesis genes, and IL-1 exposure triggers aberrant protein synthesis and cell cycle activity in PU.1-deficient HSCs. These features are associated with expansion of phenotypic PU.1-deficient HSCs. Thus, we identify a PU.1-dependent mechanism triggered by innate immune stimulation that limits HSC proliferation and pool size. These findings provide insight into how HSCs maintain homeostasis during inflammatory stress. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000480362Publication status
publishedExternal links
Journal / series
Journal of Experimental MedicineVolume
Pages / Article No.
Publisher
Rockefeller University PressOrganisational unit
03992 - Schroeder, Timm / Schroeder, Timm
Funding
179490 - Molecular dynamics in hematopoietic stem and progenitor cell fate control (SNF)
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Show all metadata
Citations
Cited 19 times in
Web of Science
Cited 23 times in
Scopus
ETH Bibliography
yes
Altmetrics