PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress.
J Exp Med
; 218(6)2021 06 07.
Article
em En
| MEDLINE
| ID: mdl-33857288
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Estresse Fisiológico
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Células-Tronco Hematopoéticas
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Transativadores
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Proteínas Proto-Oncogênicas
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Inflamação
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article