Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function
Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function
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DOI：
10.1038/nature11368
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发表时间：
2012-09-27
期刊：
影响因子：
64.8
通讯作者：
Patel, Ketan J.
中科院分区：
文献类型：
--
作者：
Garaycoechea, Juan I.;Crossan, Gerry P.;Patel, Ketan J.
造血干细胞(HSCs)在生物体的整个生命周期内再生血细胞。随着年龄的增长，造血干细胞的功能质量下降，部分原因是受损DNA的积累(1-3)。然而，破坏DNA的因素和在这些细胞中运行的保护机制却知之甚少。我们最近已经证明Fanconi贫血DNA修复途径可以抵消反应性醛的遗传毒性效应(4，5)。醛分解代谢(通过ALDH2基因敲除)和Fanconi贫血DNA修复途径(FANCD2基因敲除)联合失活的小鼠表现出发育缺陷，易患白血病，并对乙醛的外源乙醇的毒性作用敏感(4)。在这里，我们报告了没有发生白血病的老年ALDH2(-/-)FANCD2(-/-)突变小鼠会自发发展为再生障碍性贫血，伴随而来的是受损DNA在造血干细胞和祖细胞(HSPC)池中的积累。出乎意料的是，我们发现只有HSPC，而不是更成熟的血液前体细胞，需要ALDH2来保护其免受乙醛毒性。此外，Aldefluor染色检测到HSPC的乙醛氧化活性是由于ALDH2，并与这种保护相关。最后，缺乏范可尼贫血途径介导的DNA修复和乙醛解毒的小鼠的HSC池减少了600多倍。因此，Fanconi贫血患者骨髓衰竭的出现可能是由于醛介导的遗传毒性局限于HSPC池。这些发现确定了内源性反应性代谢物和HSCs中DNA损伤之间的新联系，并确定了对抗这一威胁的保护机制。
Haematopoietic stem cells (HSCs) regenerate blood cells throughout the lifespan of an organism. With age, the functional quality of HSCs declines, partly owing to the accumulation of damaged DNA(1-3). However, the factors that damage DNA and the protective mechanisms that operate in these cells are poorly understood. We have recently shown that the Fanconi anaemia DNA-repair pathway counteracts the genotoxic effects of reactive aldehydes(4,5). Mice with combined inactivation of aldehyde catabolism (through Aldh2 knockout) and the Fanconi anaemia DNA-repair pathway (Fancd2 knockout) display developmental defects, a predisposition to leukaemia, and are susceptible to the toxic effects of ethanol-an exogenous source of acetaldehyde(4). Here we report that aged Aldh2(-/-) Fancd2(-/-) mutant mice that do not develop leukaemia spontaneously develop aplastic anaemia, with the concomitant accumulation of damaged DNA within the haematopoietic stem and progenitor cell (HSPC) pool. Unexpectedly, we find that only HSPCs, and not more mature blood precursors, require Aldh2 for protection against acetaldehyde toxicity. Additionally, the aldehyde-oxidizing activity of HSPCs, as measured by Aldefluor stain, is due to Aldh2 and correlates with this protection. Finally, there is more than a 600-fold reduction in the HSC pool of mice deficient in both Fanconi anaemia pathway-mediated DNA repair and acetaldehyde detoxification. Therefore, the emergence of bone marrow failure in Fanconi anaemia is probably due to aldehyde-mediated genotoxicity restricted to the HSPC pool. These findings identify a new link between endogenous reactive metabolites and DNA damage in HSCs, and define the protective mechanisms that counteract this threat.