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内源性化物的基因毒性后果对小鼠血造干细胞功能

Juan I Garaycoechea¹, Gerry P Crossan, Frederic Langevin

¹MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.

|August 28, 2012

概括

衰老的造血干细胞 (HSCs) 由于反应性化物而积累DNA损伤. 芬科尼贫血DNA修复途径和化物解毒保护HSC,防止骨髓衰竭.

科学领域:

血液学血液学血液学
修复DNA修复DNA的修复
生物老龄化生物老龄化

背景情况:

造血干细胞 (HSC) 对于终身血液再生至关重要.
HSC功能随着年龄的增长而下降,部分原因是DNA损伤的积累.
导致DNA损伤的因素和高细胞的保护机制尚未完全理解.

研究的目的:

调查化物排毒和Fanconi贫血DNA修复途径在HSC保护中的作用.
了解与年龄相关的骨髓衰竭背后的机制.

主要方法:

使用了Aldh2淘汰 (甲基化解) 和Fancd2淘汰 (Fanconi贫血路径) 的小鼠模型.
分析了血液造血干细胞和原生细胞 (HSPC) 中的DNA损伤积累.
在HSPC中使用Aldefluor染料评估阿尔德氧化活性.

主要成果:

年龄较大的Aldh2(-/-)Fancd2(-/-) 小鼠在HSPC中发展出无塑性贫血,并积累了HSPC中的DNA损伤.
HSPCs,但不是成熟的血液前体,需要Aldh2来防止乙甲毒性.
在HSPC中,氧化活性依赖于Aldh2并与保护相关.
综合的缺陷导致HSC池减少了600倍以上.

结论:

阿尔代介导的基因毒性,仅限于HSPC池,可能导致Fanconi贫血的骨髓衰竭.
确定了内源性反应性代谢物,HSC中的DNA损伤和保护机制之间的联系.

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