Hepatocytes are replenished gradually during homeostasis and robustly after liver injury1, 2. In adults, new hepatocytes originate from the existing hepatocyte pool3–8, but the cellular source of renewing hepatocytes remains unclear. Telomerase is expressed in many stem cell populations, and mutations in telomerase pathway genes have been linked to liver diseases9–11. Here we identify a subset of hepatocytes that expresses high levels of telomerase and show that this hepatocyte subset repopulates the liver during homeostasis and injury. Using lineage tracing from the telomerase reverse transcriptase (Tert) locus in mice, we demonstrate that rare hepatocytes with high telomerase expression (TERTHigh hepatocytes) are distributed throughout the liver lobule. During homeostasis, these cells regenerate hepatocytes in all lobular zones, and both self-renew and differentiate to yield expanding hepatocyte clones that eventually dominate the liver. In response to injury, the repopulating activity of TERTHigh hepatocytes is accelerated and their progeny cross zonal boundaries. RNA sequencing shows that metabolic genes are downregulated in TERTHigh hepatocytes, indicating that metabolic activity and repopulating activity may be segregated within the hepatocyte lineage. Genetic ablation of TERTHigh hepatocytes combined with chemical injury causes a marked increase in stellate cell activation and fibrosis. These results provide support for a ‘distributed model’ of hepatocyte renewal in which a subset of hepatocytes dispersed throughout the lobule clonally expands to maintain liver mass.A population of hepatocytes expressing high levels of telomerase are distributed throughout the liver and regenerate the liver during homeostasis and after injury.

中文翻译：

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表达端粒酶的分布肝细胞在体内平衡和损伤中重新填充肝脏

肝细胞在体内平衡过程中逐渐补充，在肝损伤后得到有力补充 1, 2。在成人中，新的肝细胞来自现有的肝细胞池 3-8，但更新肝细胞的细胞来源仍不清楚。端粒酶在许多干细胞群中表达，端粒酶通路基因的突变与肝脏疾病有关 9-11。在这里，我们确定了表达高水平端粒酶的肝细胞子集，并表明该肝细胞子集在体内平衡和损伤期间重新填充肝脏。使用来自小鼠端粒酶逆转录酶 (Tert) 基因座的谱系追踪，我们证明了具有高端粒酶表达的稀有肝细胞（TERTHigh 肝细胞）分布在整个肝小叶中。在体内平衡期间，这些细胞在所有小叶区再生肝细胞，并且自我更新和分化以产生最终支配肝脏的扩大的肝细胞克隆。作为对损伤的反应，TERTHigh 肝细胞的再增殖活性被加速并且它们的后代跨越区域边界。RNA 测序显示代谢基因在 TERTHigh 肝细胞中下调，表明代谢活动和再增殖活动可能在肝细胞谱系内分离。TERTHigh 肝细胞的遗传消融结合化学损伤导致星状细胞活化和纤维化显着增加。这些结果为肝细胞更新的“分布式模型”提供了支持，在该模型中，分散在整个小叶中的肝细胞亚群克隆扩张以维持肝脏质量。