4-Hydroxynonenal inhibits cell proliferation and alters differentiation pathways in human fetal liver hematopoietic stem cells.

4-Hydroxynonenal inhibits cell proliferation and alters differentiation pathways in human fetal liver hematopoietic stem cells.
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4-Hydroxynonenal 抑制细胞增殖并改变人胎肝造血干细胞的分化途径。

DOI:
10.1016/j.bcp.2004.09.001
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发表时间:
2005
影响因子:
5.8
通讯作者:
Gallagher,EvanP
Gallagher,EvanP
中科院分区:
医学2区
文献类型:
--
作者:
Moneypenny,CraigG;Gallagher,EvanP

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在胎儿发育期间,肝脏作为主要造血器官,其中造血干细胞(HSC)构成大比例的肝细胞群。由于HSC能够启动长期造血,这些细胞的损伤可能与血源性疾病的病因学有关。在目前的研究中,我们研究了4-羟基壬烯醛(4-HNE),一种可在子宫内产生的致突变α,β-不饱和醛,对HSC增殖,分化,活力和凋亡的影响。HSC暴露于低至1 nM的急性单剂量4-HNE可抑制HSC增殖。由于4-HNE从培养基中迅速消失,因此还采用了多次给药方案,以接近与生理氧化应激相关的短期稳态4-HNE浓度。4-低至1μM的羟基壬烯醛稳态浓度改变了HSC分化途径,但不影响凋亡或引起细胞死亡。相比之下,暴露于稳态5μM 4-HNE引起存活力的丧失,并增加总HSC群体的凋亡率。总的来说,我们的数据表明,与低水平的氧化应激相关的细胞水平的4-HNE导致增殖和活力的损失,并改变人胎儿HSC的分化途径。
During fetal development, the liver serves as the primary hematopoietic organ in which hematopoietic stem cells (HSC) comprise a large proportion of hepatic cell populations. Because HSC are capable of initiating long-term hematopoiesis, injury to these cells may have ramifications with regard to the etiology of blood-borne diseases. In the current study, we examined the effects of 4-hydroxynonenal (4-HNE), a mutagenic α,β-unsaturated aldehyde that can be produced in utero, on HSC proliferation, differentiation, viability and apoptosis. Exposure of HSC to acute single doses of 4-HNE as low as 1nM inhibited HSC proliferation. Because 4-HNE rapidly disappears from culture media, a multiple dosing régime was also employed to approximate short-term steady state 4-HNE concentrations relevant to physiological oxidative stress. 4-Hydroxynonenal steady state concentrations as low as 1μM altered HSC differentiation pathways, but did not affect apoptosis or cause cell death. In contrast, exposure to steady state 5μM 4-HNE elicited a loss in viability, and increased the rate of apoptosis in total HSC populations. Collectively, our data indicate that cellular levels of 4-HNE associated with a low level of oxidative stress cause a loss of proliferation and viability and alter differentiation pathways in human fetal HSC.
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