Ueno Masaya, Itoh Machiko, Sugihara Kazushi, Asano Masahide, Takakura Nobuyuki
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
Blood. 2009 Jan 15;113(3):555-62. doi: 10.1182/blood-2008-01-136879. Epub 2008 Nov 4.
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.
造血干细胞（HSCs）在稳态下细胞分裂率非常低；然而，在造血应激条件下，这些细胞可开始高速增殖，分化为成熟造血细胞，并迅速重建被破坏的骨髓（BM）。此前，我们从一个HSC特异性cDNA文库中分离出一种新的进化保守DNA复制因子PSF1（SLD5-1的伙伴）。在稳态下，PSF1主要在CD34(+)KSL（c-kit(+)/Sca-1(+)/谱系(-)）细胞和祖细胞中表达，而在骨髓消融后，KSL细胞中会诱导高水平的PSF1表达。在1岁的PSF1(+/-)小鼠中，干细胞和祖细胞的池大小减小。虽然年轻的PSF1(+/-)突变小鼠发育正常、可育，且与野生型小鼠相比在稳态下造血无明显差异，但静脉注射5-氟尿嘧啶（5-FU）对PSF1(+/-)小鼠是致命的，这是由于在被破坏的骨髓重建过程中HSC增殖诱导延迟所致。过表达研究表明，PSF1调节包括SLD5、PSF2和PSF3在内的其他GINS成分的分子稳定性。我们的数据表明，PSF1是小鼠骨髓中HSC急性增殖所必需的。
