Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO.
Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule Zurich, Basel, Switzerland.
J Exp Med. 2021 Jun 7;218(6). doi: 10.1084/jem.20201169.
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.
造血干细胞（HSCs）能够进入细胞周期，以响应炎症信号来补充血液系统；然而，过度增殖会导致 HSC 耗竭或扩增。目前，人们对炎症信号触发的 HSC 增殖和扩增所受限制的机制知之甚少。在这里，我们发现，长期造血干细胞（HSCLT）在受到促炎细胞因子白细胞介素（IL）-1 处理后，会迅速抑制蛋白质合成和细胞周期基因的表达。该基因程序与转录因子 PU.1 的激活以及受抑制靶基因的直接 PU.1 结合有关。值得注意的是，PU.1 对于抑制细胞周期和蛋白质合成基因的表达是必需的，而 IL-1 暴露会引发 PU.1 缺陷型 HSCs 中异常的蛋白质合成和细胞周期活性。这些特征与表型 PU.1 缺陷型 HSCs 的扩增有关。因此，我们确定了一种由先天免疫刺激触发的、依赖于 PU.1 的机制，该机制限制了 HSC 的增殖和池大小。这些发现为了解 HSCs 在炎症应激期间如何维持体内平衡提供了线索。
