Human AK2 links intracellular bioenergetic redistribution to the fate of hematopoietic progenitors
Human AK2 links intracellular bioenergetic redistribution to the fate of hematopoietic progenitors
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DOI：
10.1016/j.bbrc.2018.02.139
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发表时间：
2018-03-04
影响因子：
3.1
通讯作者：
Saito, Megumu K.
中科院分区：
文献类型：
--
作者：
Oshima, Koichi;Saiki, Norikazu;Saito, Megumu K.
AK 2是一种腺苷酸磷酸转移酶，定位于线粒体的膜间隙，其突变导致严重的联合免疫缺陷伴中性粒细胞成熟停滞，称为网状细胞发育不全（RD）。虽然造血干细胞（HSC）的功能障碍已被牵连，影响造血干细胞和/或造血祖细胞的命运的早期发育事件尚未报道。在这里，我们使用RD患者来源的诱导多能干细胞（iPSC）作为AK 2缺陷型人类细胞的模型。来自RD-iPSC的造血分化严重受损。RD-iPSC衍生的血血管生成祖细胞（HAPC）显示出细胞核中ATP分布减少和全局转录谱改变。因此，AK 2在造血分化过程中维持ATP向细胞核的供应方面具有阶段特异性作用，这影响了控制多能HAPC命运所必需的转录谱。我们的数据表明，维持适当的能量水平的每个细胞器的细胞内重新分配的ATP是重要的控制祖细胞的命运。(C)2018作者爱思唯尔公司出版
AK2 is an adenylate phosphotransferase that localizes at the intermembrane spaces of the mitochondria, and its mutations cause a severe combined immunodeficiency with neutrophil maturation arrest named reticular dysgenesis (RD). Although the dysfunction of hematopoietic stem cells (HSCs) has been implicated, earlier developmental events that affect the fate of HSCs and/or hematopoietic progenitors have not been reported. Here, we used RD-patient-derived induced pluripotent stem cells (iPSCs) as a model of AK2-deficient human cells. Hematopoietic differentiation from RD-iPSCs was profoundly impaired. RD-iPSC-derived hemoangiogenic progenitor cells (HAPCs) showed decreased ATP distribution in the nucleus and altered global transcriptional profiles. Thus, AK2 has a stage-specific role in maintaining the ATP supply to the nucleus during hematopoietic differentiation, which affects the transcriptional profiles necessary for controlling the fate of multipotential HAPCs. Our data suggest that maintaining the appropriate energy level of each organelle by the intracellular redistribution of ATP is important for controlling the fate of progenitor cells. (C) 2018 The Authors. Published by Elsevier Inc.