Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK.
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK.
Mol Cell. 2023 Jul 20;83(14):2417-2433.e7. doi: 10.1016/j.molcel.2023.05.035. Epub 2023 Jun 21.
Aged hematopoietic stem cells (HSCs) display diminished self-renewal and a myeloid differentiation bias. However, the drivers and mechanisms that underpin this fundamental switch are not understood. HSCs produce genotoxic formaldehyde that requires protection by the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. We find that the HSCs in young Aldh2Fancd2 mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition, and myeloid-biased differentiation quantified by single HSC transplantation. In addition, the p53 response is vigorously activated in Aldh2Fancd2 HSCs, while p53 deletion rescued this aged HSC phenotype. To further define the origins of the myeloid differentiation bias, we use a GFP genetic reporter to find a striking enrichment of Vwf+ myeloid and megakaryocyte-lineage-biased HSCs. These results indicate that metabolism-derived formaldehyde-DNA damage stimulates the p53 response in HSCs to drive accelerated aging.
衰老的造血干细胞（HSCs）表现出自我更新能力下降和偏向髓系分化。然而，支撑这种基本转变的驱动因素和机制尚不清楚。HSCs 会产生具有遗传毒性的甲醛，需要解毒酶 ALDH2 和 ADH5 以及范可尼贫血（FA）DNA 修复途径来保护。我们发现，年轻 Aldh2Fancd2 小鼠中的 HSCs 具有与老年野生型 HSCs 相当的转录组特征，同时伴随着表观遗传年龄增加、端粒磨损以及通过单个 HSC 移植定量的偏向髓系分化。此外，Aldh2Fancd2 HSCs 中 p53 反应被强烈激活，而 p53 缺失则挽救了这种衰老 HSC 表型。为了进一步确定偏向髓系分化的起源，我们使用 GFP 遗传报告基因发现，Vwf+髓系和巨核细胞谱系偏向的 HSCs 显著富集。这些结果表明，代谢产生的甲醛-DNA 损伤刺激 HSCs 中的 p53 反应，从而导致加速衰老。
