Lineage fate of ductular reactions in liver injury and carcinogenesis
Lineage fate of ductular reactions in liver injury and carcinogenesis
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DOI：
10.1172/jci78585
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发表时间：
2015-06-01
影响因子：
15.9
通讯作者：
Geisler, Fabian
中科院分区：
文献类型：
--
作者：
Joers, Simone;Jeliazkova, Petia;Geisler, Fabian
几乎在所有形式的人类肝病中都观察到了小管反应（DR）;然而，DR在肝损伤中的组织发生和功能尚未完全了解。人们普遍认为，DR含有双能肝祖细胞（LPC），作为一个应急细胞池，以再生胆管细胞和肝细胞，并可能最终导致肝细胞癌（HCC）。在这里，我们使用了一个小鼠模型，允许高效和特异性的谱系标记的胆管室，以分析DR的组织发生及其对肝再生和癌变的潜在贡献。在多种实验和遗传性肝损伤模型中，胆管细胞是DR的主要前体，但缺乏产生新肝细胞的实质性能力，即使肝损伤延长至12个月。在谱系标记的DR中，NOTCH和/或WNT/β-连环蛋白信号传导的遗传调节损害了DR扩增，但未能将DR从胆管分化重定向到肝细胞谱系。此外，谱系标记的DR在遗传和化学HCC小鼠模型中不产生肿瘤。总之，我们在我们的系统中没有发现证据支持小鼠胆汁来源的DR作为LPC池以定量相关的方式补充肝细胞损伤或DR引起HCC的证据。
Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however, the histogenesis and function of DRs in liver injury are not entirely understood. It is widely believed that DRs contain bipotential liver progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both cholangiocytes and hepatocytes and may eventually give rise to hepatocellular carcinoma (HCC). Here, we used a murine model that allows highly efficient and specific lineage labeling of the biliary compartment to analyze the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. In multiple experimental and genetic liver injury models, biliary cells were the predominant precursors of DRs but lacked substantial capacity to produce new hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic modulation of NOTCH and/or WNT/beta-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to redirect DRs from biliary differentiation toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. In summary, we found no evidence in our system to support mouse biliary-derived DRs as an LPC pool to replenish hepatocytes in a quantitatively relevant way in injury or evidence that DRs give rise to HCCs.