STAT1 is essential for hematopoietic stem cell function and maintains a MHC IIhi stem cell subset that resists myeloablation and neoplastic expansion [LK]. STAT1 is essential for hematopoietic stem cell function and maintains a MHC IIhi stem cell subset that resists myeloablation and neoplastic expansion [LK]

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 mediator of interferon (IFN) signaling and is required for IFN-induced HSC proliferation, but the downstream mechanisms remain unclear and in particular little is known about the role of STAT1 in regulating hematopoietic stem/progenitor cells during homeostasis. Here we show that loss of STAT1 alters the steady state hematopoietic stem and progenitor (HSPC) landscape, impairs HSC function in transplantation assays and delays blood cell regeneration following myeloablation. Under steady state conditions STAT1 was essential for several HSC transcriptional programs including expression of genes involved in virus life cycle, a subset of interferon-stimulated genes, MHC class I genes and genes involved in cell cycle arrest. In addition Stat-1 deficient mice lacked a previously unrecognized quiescent subset of homeostatic HSCs with high levels of MHC II expression (MHC IIhi HSCs). This subset was refractory to 5’-FU induced myeloablation and displayed reduced megakaryocytic potential. Mutant calreticulin, which causes increased megakaryopoiesis in human myeloproliferative neoplasms, gave rise to preferential expansion of MHC IIlo HSCs. These data reveal a STAT1 dependent MHC IIhi quiescent HSC subset and show that STAT1 protects HSCs from proliferative exhaustion. Overall design: Bone marrow cells were harvested from STAT1KO and WT control mice, lineage negative cKit positive LK cells (lin-cKit+) were sorted

成人造血干细胞（hematopoietic stem cells, HSCs）大多处于静息状态，可在感染或细胞毒性损伤等急性应激条件下被激活。信号转导与转录激活因子1（STAT1）是干扰素（interferon, IFN）信号通路的关键介导因子，对于干扰素诱导的造血干细胞增殖必不可少，但其下游调控机制仍不明确，尤其在稳态条件下，STAT1对造血干/祖细胞的调控作用尚鲜为人知。本研究发现，STAT1缺失会改变稳态下造血干/祖细胞（hematopoietic stem and progenitor cells, HSPCs）的组成格局，损害移植实验中的造血干细胞功能，并延迟骨髓清除术后的血细胞再生。在稳态条件下，STAT1对于多项造血干细胞转录程序至关重要，其中包括病毒生命周期相关基因的表达、一类干扰素刺激基因、主要组织相容性复合体I类（MHC class I）基因，以及参与细胞周期阻滞的基因。此外，STAT1敲除小鼠缺乏此前未被识别的、高表达主要组织相容性复合体II类（MHC class II）的稳态造血干细胞静息亚群（MHC IIhi HSCs）。该亚群对5'-氟尿嘧啶（5'-FU）诱导的骨髓清除具有抗性，且表现出减弱的巨核细胞分化潜能。突变型钙网蛋白可导致人类骨髓增殖性肿瘤中巨核细胞生成增多，其能优先促进MHC II低表达造血干细胞（MHC IIlo HSCs）的扩增。上述研究结果揭示了一种依赖STAT1的MHC II高表达静息造血干细胞亚群，并表明STAT1可保护造血干细胞免于增殖耗竭。实验整体设计：从STAT1敲除（STAT1KO）与野生型（WT）对照小鼠中获取骨髓细胞，分选谱系阴性cKit阳性LK细胞（lin⁻cKit⁺细胞）。