Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer.
Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer.
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DOI：
10.1016/j.cell.2015.07.026
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发表时间：
2015-08-13
期刊：
影响因子：
64.5
通讯作者：
Karin M
中科院分区：
文献类型：
--
作者：
Font-Burgada J;Shalapour S;Ramaswamy S;Hsueh B;Rossell D;Umemura A;Taniguchi K;Nakagawa H;Valasek MA;Ye L;Kopp JL;Sander M;Carter H;Deisseroth K;Verma IM;Karin M
肝细胞损失引发的代偿性增殖是肝脏再生和维护所必需的，但也会促进肝细胞癌（HCC）的发展。尽管进行了广泛的研究，但负责肝细胞恢复或 HCC 发展的细胞仍然知之甚少。我们使用遗传谱系追踪来识别慢性肝损伤后负责肝细胞补充的细胞，并询问它们在三种不同 HCC 模型中的作用。我们发现，预先存在的门静脉周围肝细胞群位于健康肝脏的门静脉三联体中，表达少量的 Sox9 和其他富含胆管的基因，在慢性肝细胞耗竭损伤后，会经历广泛的增殖并补充肝脏质量。尽管它们具有很高的再生潜力，但这些所谓的混合肝细胞不会在慢性损伤的肝脏中引起肝癌，因此代表了恢复组织功能和避免肿瘤发生的独特方法。这组专门的预先存在的分化细胞可能非常适合慢性肝细胞耗竭性疾病的细胞疗法。
Compensatory proliferation triggered by hepatocyte loss is required for liver regeneration and maintenance but also promotes development of hepatocellular carcinoma (HCC). Despite extensive investigation, the cells responsible for hepatocyte restoration or HCC development remain poorly characterized. We used genetic lineage tracing to identify cells responsible for hepatocyte replenishment following chronic liver injury and queried their roles in three distinct HCC models. We found that a pre-existing population of periportal hepatocytes, located in the portal triads of healthy livers and expressing low amounts of Sox9 and other bile-duct-enriched genes, undergo extensive proliferation and replenish liver mass after chronic hepatocyte-depleting injuries. Despite their high regenerative potential, these so-called hybrid hepatocytes do not give rise to HCC in chronically injured livers and thus represent a unique way to restore tissue function and avoid tumorigenesis. This specialized set of pre-existing differentiated cells may be highly suitable for cell-based therapy of chronic hepatocyte-depleting disorders.