Both alleles of PSF1 are required for maintenance of pool size of immature hematopoietic cells and acute bone marrow regeneration
Both alleles of PSF1 are required for maintenance of pool size of immature hematopoietic cells and acute bone marrow regeneration
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DOI：
10.1182/blood-2008-01-136879
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发表时间：
2009-01-15
期刊：
影响因子：
20.3
通讯作者：
Takakura, Nobuyuki
中科院分区：
文献类型：
--
作者：
Ueno, Masaya;Itoh, Machiko;Takakura, Nobuyuki
造血干细胞(HSCs)在稳定状态下的细胞分裂率很低，但在造血应激条件下，这些细胞可以开始高速增殖，分化为成熟的造血细胞，并迅速重建骨髓(BM)。此前，我们从HSC特异的cDNA文库中克隆了一个新的进化保守的DNA复制因子PSF1(SLD5-1的伙伴)。在稳定状态下，PSF1主要在CD34(+)KSL(c-kit(+)/SCA-1(+)/Lineage(-))细胞和祖细胞中表达，而BM消融后KSL细胞高水平表达PSF1。在1岁的PSF1(+/-)小鼠中，干细胞和祖细胞的池大小减少。尽管年轻的PSF1(+/-)突变小鼠发育正常，生育能力强，稳态时的造血功能与野生型小鼠没有明显差异，但静脉注射5-氟尿嘧啶(5-FU)对PSF1(+/-)小鼠是致命的，这是由于骨髓消融重建过程中HSC增殖诱导的延迟造成的。过表达研究表明，PSF1调节其他GINS组分的分子稳定性，包括SLD5、PSF2和PSF3。我们的数据表明，PSF1是小鼠骨髓中HSCs急性增殖所必需的。(血。2009；113：555-562)
Hematopoietic stem cells (HSCs) have a very low rate of cell division in the steady state; however, under conditions of hematopoietic stress, these cells can begin to proliferate at high rates, differentiate into mature hematopoietic cells, and rapidly reconstitute ablated bone marrow (BM). Previously, we isolated a novel evolutionarily conserved DNA replication factor, PSF1 (partner of SLD5-1), from an HSC-specific cDNA library. In the steady state, PSF1 is expressed predominantly in CD34(+) KSL (c-kit(+)/Sca-1(+)/Lineage(-)) cells and progenitors, whereas high levels of PSF1 expression are induced in KSL cells after BM ablation. In 1-year-old PSF1(+/-) mice, the pool size of stem cells and progenitors is decreased. Whereas young PSF1(+/-) mutant mice develop normally, are fertile, and have no obvious differences in hematopoiesis in the steady state compared with wild-type mice, intravenous injection of 5-fluorouracil (5-FU) is lethal in PSF1(+/-) mice, resulting from a delay in induction of HSC proliferation during ablated BM reconstitution. Overexpression studies revealed that PSF1 regulates molecular stability of other GINS components, including SLD5, PSF2, and PSF3. Our data indicate that PSF1 is required for acute proliferation of HSCs in the BM of mice. (Blood. 2009; 113: 555-562)