Abstract：
Chronic liver injury induces liver cirrhosis and facilitates hepatocarcinogenesis. However, the effects of this condition on hepatocyte proliferation and differentiation are unclear. We showed that rodent hepatocytes display a ductular phenotype when they are cultured within a collagenous matrix. This process involves transdifferentiation without the emergence of hepatoblastic features and is at least partially reversible. During the ductular reaction in chronic liver diseases with progressive fibrosis, some hepatocytes, especially those adjacent to ectopic ductules, demonstrate ductular transdifferentiation, but the majority of increased ductules originate from the existing bile ductular system that undergoes extensive remodeling. In chronic injury, hepatocyte proliferation is weak but sustained, and most regenerative nodules in liver cirrhosis are composed of clonally proliferating hepatocytes, suggesting that a small fraction of hepatocytes maintain their proliferative capacity in chronic injury. In mouse hepatocarcinogenesis models, hepatocytes activate the expression of various fetal/neonatal genes, indicating that these cells undergo dedifferentiation. Hepatocyte-specific somatic integration of various oncogenes in mice demonstrated that hepatocytes may be the cells of origin for a broad spectrum of liver tumors through transdifferentiation and dedifferentiation. In conclusion, the phenotypic plasticity and heterogeneity of mature hepatocytes are important for understanding the pathogenesis of chronic liver diseases and liver tumors.
摘要：
慢性肝损伤诱导肝硬化并促进肝癌发生。然而,这种情况对肝细胞增殖和分化的影响尚不清楚。我们表明，啮齿动物肝细胞在胶原基质中培养时表现出导管表型。该过程涉及转分化而不出现肝母细胞特征，并且至少是部分可逆的。在慢性肝病进行性纤维化的导管反应期间，一些肝细胞，尤其是那些邻近异位导管的，显示导管转分化，但是大多数增加的小导管起源于经历广泛重塑的现有胆管系统。在慢性损伤中，肝细胞增殖较弱但持续，肝硬化中的大多数再生结节由无性系增殖的肝细胞组成，表明一小部分肝细胞在慢性损伤中保持其增殖能力。在小鼠肝癌模型中，肝细胞激活各种胎儿/新生儿基因的表达，表明这些细胞经历去分化。小鼠中各种癌基因的肝细胞特异性体细胞整合表明，肝细胞可能是通过转分化和去分化的广谱肝肿瘤的起源细胞。总之,成熟肝细胞的表型可塑性和异质性对理解慢性肝病和肝肿瘤的发病机制具有重要意义。
