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 that protect HSCs, including control of quiescence. Our results also reveal STAT1-dependent functional HSC heterogeneity. A previously unrecognized subset of homeostatic HSCs with elevated major histocompatibility complex class II (MHCII) expression (MHCIIhi) displayed molecular features of reduced cycling and apoptosis and was refractory to 5-fluorouracil-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.

中文翻译：

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STAT1 对于 HSC 功能至关重要，并维持 MHCIIhi 干细胞抵抗清髓和肿瘤扩张。


成体造血干细胞（HSC）主要处于静止状态，可以响应感染或细胞毒性损伤等急性应激而被激活。 STAT1 是干扰素 (IFN) 信号传导的关键下游介质，是 IFN 诱导的 HSC 增殖所必需的，但人们对 STAT1 在调节稳态造血干/祖细胞 (HSPC) 中的作用知之甚少。在这里，我们发现 STAT1 的缺失改变了 HSPC 的稳态格局，移植试验中 HSC 功能受损，清髓后血细胞再生延迟，并破坏了保护 HSC 的分子程序，包括静止控制。我们的结果还揭示了 STAT1 依赖性 HSC 功能异质性。先前未被识别的稳态 HSC 亚群具有升高的主要组织相容性复合物 II 类 (MHCII) 表达 (MHCIIhi)，显示出循环和细胞凋亡减少的分子特征，并且对 5-氟尿嘧啶诱导的清髓无效。相反，MHCIIlo HSC 显示出增加的巨核细胞潜力，并且在具有血小板增多症的 CALR 突变小鼠中优先扩增。与小鼠类似，MHCII 高表达是人类 HSC 处于更深静止状态的一个特征。因此，我们的结果将 STAT1 定位在干细胞异质性以及干细胞与适应性免疫系统之间相互作用的界面上，这是更广泛的干细胞领域中广泛关注的领域。