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

AI Article Synopsis

  • Hematopoietic stem cells (HSCs) can proliferate to replenish blood cells in response to inflammation but can either decrease in number (attrition) or increase excessively (expansion) with chronic inflammation.
  • The study found that long-term HSCs quickly reduce protein production and cell cycle activity when exposed to the inflammatory cytokine interleukin (IL)-1, a process involving the transcription factor PU.1.
  • PU.1 is crucial for repressing genes related to cell division and protein synthesis; without it, HSCs show abnormal activity and excessive expansion, highlighting how HSCs regulate their growth in response to immune signals.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056754PMC
http://dx.doi.org/10.1084/jem.20201169DOI Listing

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