Lu Kenneth, Nakagawa Masahiro Marshall, Thummar Keyur, Rathinam Chozha Vendan
Department of Genetics and Development, Columbia University Medical Center, New York, New York, USA.
Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.
Stem Cells. 2016 May;34(5):1343-53. doi: 10.1002/stem.2302. Epub 2016 Mar 28.
Hematopoietic stem cells (HSCs) are capable of both self-renewing throughout the lifetime of an organism and differentiating into all lineages of the blood system. A proper balance between quiescence and proliferation is critical for the self-renewal and functions of HSCs. The choice of HSCs to remain quiescent or to enter proliferation has been tightly regulated by a variety of cell intrinsic and extrinsic pathways. Identifying molecular players that control HSC quiescence and proliferation may lead to new treatment strategies and therapeutic interventions for hematologic disorders. To identify the functions of the slicer endonuclease Argonaute (Ago) 2 in the physiology of HSCs, we generated Ago2(Hem-KO) mice, that are deficient for Ago2 in HSCs and in their progeny. Analysis of Ago2(Hem-KO) mice indicated that a loss of Ago2 results in reduced HSC pool size and altered frequencies of hematopoietic progenitors. Ago2 deficient HSCs exhibit defective multilineage differentiation capacities and diminished repopulation abilities, in a cell intrinsic manner. Interestingly, Ago2 mutant HSCs remain largely quiescent and show reduced entry into cell cycle. Genome-wide transcriptome studies and gene set enrichment analysis revealed that Ago2 deficient HSCs downregulate the "HSC signature" and upregulate the "lineage signature." Moreover, our analysis on transcription factors (TFs) identified that a loss of Ago2 is sufficient to alter the "molecular signature" and "TF networks" that control the quiescent and proliferative states of HSCs. In essence, our study identified Ago2 as a key determinant of quiescence exit in HSCs. Stem Cells 2016;34:1343-1353.
造血干细胞（HSCs）能够在生物体的整个生命周期内自我更新，并分化为血液系统的所有谱系。静止与增殖之间的适当平衡对于造血干细胞的自我更新和功能至关重要。造血干细胞选择保持静止或进入增殖状态受到多种细胞内在和外在途径的严格调控。识别控制造血干细胞静止和增殖的分子参与者可能会带来针对血液系统疾病的新治疗策略和治疗干预措施。为了确定核酸内切酶Argonaute（Ago）2在造血干细胞生理学中的功能，我们构建了Ago2（Hem-KO）小鼠，其造血干细胞及其后代中缺乏Ago2。对Ago2（Hem-KO）小鼠的分析表明，Ago2的缺失导致造血干细胞池大小减小以及造血祖细胞频率改变。缺乏Ago2的造血干细胞以细胞内在方式表现出有缺陷的多谱系分化能力和减弱的再增殖能力。有趣的是，Ago2突变的造血干细胞在很大程度上保持静止，并显示进入细胞周期的减少。全基因组转录组研究和基因集富集分析表明，缺乏Ago2的造血干细胞下调“造血干细胞特征”并上调“谱系特征”。此外，我们对转录因子（TFs）的分析确定，Ago2的缺失足以改变控制造血干细胞静止和增殖状态的“分子特征”和“TF网络”。本质上，我们的研究确定Ago2是造血干细胞静止退出的关键决定因素。《干细胞》2016年；34：1343 - 1353。
