Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
Division of Transplant Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Sci Adv. 2020 Jan 31;6(5):eaax2659. doi: 10.1126/sciadv.aax2659. eCollection 2020 Jan.
Accumulating somatic mutations have been implicated in age-related cellular degeneration and death. Because of their random nature and low abundance, somatic mutations are difficult to detect except in single cells or clonal cell lineages. Here, we show that in single hepatocytes from human liver, an organ exposed to high levels of genotoxic stress, somatic mutation frequencies are high and increase substantially with age. Considerably lower mutation frequencies were observed in liver stem cells (LSCs) and organoids derived from them. Mutational spectra in hepatocytes showed signatures of oxidative stress that were different in old age and in LSCs. A considerable number of mutations were found in functional parts of the liver genome, suggesting that somatic mutagenesis could causally contribute to the age-related functional decline and increased incidence of disease of human liver. These results underscore the importance of stem cells in maintaining genome sequence integrity in aging somatic tissues.
体细胞突变的积累与年龄相关的细胞退化和死亡有关。由于其随机性和低丰度，体细胞突变除了在单细胞或克隆细胞谱系中很难检测到。在这里，我们表明，在人类肝脏的单个肝细胞中，一种暴露于高水平遗传毒性应激的器官，体细胞突变频率很高，并且随着年龄的增长而显著增加。在肝干细胞 (LSCs) 及其衍生的类器官中观察到的突变频率要低得多。肝细胞中的突变谱显示出氧化应激的特征，这些特征在老年和 LSCs 中有所不同。在肝脏基因组的功能部分发现了相当数量的突变，这表明体细胞突变可能会导致人类肝脏的功能下降和疾病发病率增加。这些结果强调了干细胞在维持衰老体组织基因组序列完整性方面的重要性。
