Reversal of Hepatocyte Senescence After Continuous In Vivo Cell Proliferation
Reversal of Hepatocyte Senescence After Continuous In Vivo Cell Proliferation
复制标题
体内细胞连续增殖后肝细胞衰老的逆转
DOI：
10.1002/hep.27094
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发表时间：
2014-07-01
期刊：
影响因子：
13.5
通讯作者：
Hu, Yi-Ping
中科院分区：
文献类型：
--
作者：
Wang, Min-Jun;Chen, Fei;Hu, Yi-Ping
更好地了解肝细胞衰老可用于治疗年龄依赖性的肝脏疾病过程。持续增殖的肝细胞是否可以避免或逆转衰老尚未完全阐明。我们证实，老年小鼠的肝脏积累了衰老和多倍体肝细胞，这与DNA损伤的积累和p53-p21和p16(ink4a)-pRB途径的激活有关。诱导多轮连续细胞分裂很难应用于任何动物模型。利用富马酰乙酰乙酸水解酶缺陷（Fah(-/-)）小鼠的连续肝细胞移植试验，我们研究了经过长时间连续细胞增殖（最多12轮连续移植）的肝细胞的衰老情况。我们证明，不断增殖的肝细胞避免了衰老，始终保持年轻状态。连续移植后肝细胞中端粒酶的重新激活与衰老的逆转相关。此外，从老年小鼠身上采集的衰老肝细胞在连续移植后变得年轻，增殖能力完全恢复。同样的发现也适用于人类肝细胞。连续移植后，八倍体肝细胞的初始高比例下降，以匹配年轻肝脏的低水平。结论：这些发现表明，肝细胞“倍性传递者”在衰老和再生过程中受到不同的调节。逆转肝细胞衰老的发现可能有助于未来关于肝脏衰老和细胞治疗的研究。
A better understanding of hepatocyte senescence could be used to treat age-dependent disease processes of the liver. Whether continuously proliferating hepatocytes could avoid or reverse senescence has not yet been fully elucidated. We confirmed that the livers of aged mice accumulated senescent and polyploid hepatocytes, which is associated with accumulation of DNA damage and activation of p53-p21 and p16(ink4a)-pRB pathways. Induction of multiple rounds continuous cell division is hard to apply in any animal model. Taking advantage of serial hepatocyte transplantation assays in the fumarylacetoacetate hydrolase-deficient (Fah(-/-)) mouse, we studied the senescence of hepatocytes that had undergone continuous cell proliferation over a long time period, up to 12 rounds of serial transplantations. We demonstrated that the continuously proliferating hepatocytes avoided senescence and always maintained a youthful state. The reactivation of telomerase in hepatocytes after serial transplantation correlated with reversal of senescence. Moreover, senescent hepatocytes harvested from aged mice became rejuvenated upon serial transplantation, with full restoration of proliferative capacity. The same findings were also true for human hepatocytes. After serial transplantation, the high initial proportion of octoploid hepatocytes decreased to match the low level of youthful liver. Conclusion: These findings suggest that the hepatocyte "ploidy conveyer" is regulated differently during aging and regeneration. The findings of reversal of hepatocyte senescence could enable future studies on liver aging and cell therapy.