Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury.
Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury.
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DOI：
10.1038/s41586-018-0004-7
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发表时间：
2018-04
期刊：
影响因子：
64.8
通讯作者：
Artandi SE
中科院分区：
文献类型：
--
作者：
Lin S;Nascimento EM;Gajera CR;Chen L;Neuhöfer P;Garbuzov A;Wang S;Artandi SE
肝细胞在体内平衡期间逐渐补充，并在肝损伤后得到强劲补充。在成人中，新的肝细胞来源于现有的肝细胞库，但更新肝细胞的细胞来源仍然不完全清楚。端粒酶在许多干细胞群体中表达，端粒酶途径基因突变与肝脏疾病有关。在这里，我们确定了一个亚组的肝细胞表达高水平的端粒酶，并表明，这个肝细胞亚组在体内平衡和损伤过程中重新填充肝脏。使用谱系追踪从端粒酶逆转录酶（Tert）基因座在小鼠中，我们证明，罕见的肝细胞与端粒酶高表达分布在整个肝小叶。在体内平衡期间，这些细胞在所有小叶区中再生肝细胞，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。在损伤反应中，TERTH高肝细胞的重建活性加速，并且其后代跨越区域边界。RNA-seq揭示了代谢基因在TERTHi肝细胞中下调，表明代谢活性和再增殖活性可能在肝细胞谱系内分离。TERTH高肝细胞的基因消融联合化学损伤导致星状细胞活化和纤维化显著增加。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性扩张以维持肝脏质量。
Hepatocytes are replenished gradually during homeostasis and robustly after liver injury. In adults, new hepatocytes originate from the existing hepatocyte pool, but the cellular source of renewing hepatocytes remains incompletely understood. Telomerase is expressed in many stem cell populations, and telomerase pathway gene mutations are linked to liver diseases. 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 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 injury responses, the repopulating activity of TERTHigh hepatocytes is accelerated and their progeny cross zonal boundaries. RNA-seq reveals that metabolic genes are down regulated 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.
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DOI：
10.1073/pnas.1013004108
发表时间：
2011-01-04
影响因子：
11.1
作者：
Montgomery, Robert K.;Carlone, Diana L.;Breault, David T.
通讯作者：
Breault, David T.
影响因子：
11.4
作者：
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通讯作者：
Clevers, Hans
影响因子：
25
作者：
Madisen L;Zwingman TA;Sunkin SM;Oh SW;Zariwala HA;Gu H;Ng LL;Palmiter RD;Hawrylycz MJ;Jones AR;Lein ES;Zeng H
通讯作者：
Zeng H
DOI：
10.1073/pnas.182412299
发表时间：
2002-09-03
影响因子：
11.1
作者：
Gao, GP;Alvira, MR;Wilson, JM
通讯作者：
Wilson, JM
影响因子：
--
作者：
Aurnhammer, Christine;Haase, Maren;Baiker, Armin
通讯作者：
Baiker, Armin