STAT1 is essential for HSC function and maintains MHCIIhi stem cells that resist myeloablation and neoplastic expansion.
STAT1 is essential for HSC function and maintains MHCIIhi stem cells that resist myeloablation and neoplastic expansion.
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DOI：
10.1182/blood.2021014009
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发表时间：
2022-10-06
期刊：
影响因子：
20.3
通讯作者：
Green AR
中科院分区：
文献类型：
--
作者：
Li J;Williams MJ;Park HJ;Bastos HP;Wang X;Prins D;Wilson NK;Johnson C;Sham K;Wantoch M;Watcham S;Kinston SJ;Pask DC;Hamilton TL;Sneade R;Waller AK;Ghevaert C;Vassiliou GS;Laurenti E;Kent DG;Göttgens B;Green AR
STAT1对于正常的HSC功能和对应激诱导增殖反应较弱的MHCIIhi HSC亚群的维持至关重要。MHCIIhi和MHCIIlo亚群都含有功能性造血干细胞，但MHCIIlo造血干细胞在突变型CALR小鼠中表现出增加的Mk潜能和扩增。成人造血干细胞（hsc）主要处于静止状态，在急性应激（如感染或细胞毒性损伤）下可被激活。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，但对STAT1在调节稳态造血干细胞/祖细胞（HSPCs）中的作用知之甚少。在这里，我们发现STAT1的缺失改变了稳定状态的HSC景观，在移植试验中损害了HSC的功能，延迟了骨髓消融后的血细胞再生，破坏了保护HSC的分子程序，包括对静止的控制。我们的研究结果还揭示了stat1依赖性功能性HSC的异质性。一种以前未被识别的稳态造血干细胞亚群，其主要组织相容性复合体II类（MHCII）表达升高（MHCIIhi），表现出循环减少和细胞凋亡的分子特征，并且对5-氟尿嘧啶诱导的骨髓消融难以耐受。相反，MHCIIlo造血干细胞显示出增加的巨核细胞潜能，并在CALR突变小鼠血小板增多症中优先扩增。与小鼠相似，高表达MHCII是人类hsc处于更深的静止状态的一个特征。因此，我们的研究结果将STAT1定位于干细胞异质性和干细胞与适应性免疫系统之间相互作用的界面，这是更广泛的干细胞领域广泛关注的领域。
STAT1 is essential for normal HSC function and maintenance of a MHCIIhi HSC subset that is less responsive to stress-induced proliferation. MHCIIhi and MHCIIlo subsets both contain functional HSCs, but MHCIIlo HSCs show increased Mk potential and are expanded in mutant CALR mice. 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.
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DOI：
10.1038/nri3062
发表时间：
2011-09-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
30.8
作者：
Dupuis, S;Jouanguy, E;Casanova, JL
通讯作者：
Casanova, JL
影响因子：
64.8
作者：
Busch, Katrin;Klapproth, Kay;Rodewald, Hans-Reimer
通讯作者：
Rodewald, Hans-Reimer
影响因子：
23.9
作者：
Dykstra, Brad;Kent, David;Eaves, Connie
通讯作者：
Eaves, Connie
影响因子：
64.8
作者：
Hock, H;Hamblen, MJ;Orkin, SH
通讯作者：
Orkin, SH