Medical Research Council Center for Regenerative Medicine, The University of Edinburgh, Edinburgh bioQuarter, Edinburgh, United Kingdom; Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata, Japan.
Hepatology. 2014 Nov;60(5):1727-40. doi: 10.1002/hep.27099. Epub 2014 Sep 29.
In severe liver injury, ductular reactions (DRs) containing bipotential hepatic progenitor cells (HPCs) branch from the portal tract. Neural cell adhesion molecule (NCAM) marks bile ducts and DRs, but not mature hepatocytes. NCAM mediates interactions between cells and surrounding matrix; however, its role in liver development and regeneration is undefined. Polysialic acid (polySia), a unique posttranslational modifier of NCAM, is produced by the enzymes, ST8SiaII and ST8SiaIV, and weakens NCAM interactions. The role of polySia with NCAM synthesizing enzymes ST8SiaII and ST8SiaIV were examined in HPCs in vivo using the choline-deficient ethionine-supplemented and 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet models of liver injury and regeneration, in vitro using models of proliferation, differentiation, and migration, and by use of mouse models with gene defects in the polysialyltransferases (St8sia 2+/-4+/-, and St8sia2-/-4-/-). We show that, during liver development, polySia is required for the correct formation of bile ducts because gene defects in both the polysialyltransferases (St8sia2+/-4+/- and St8sia2-/-4-/- mice) caused abnormal bile duct development. In normal liver, there is minimal polySia production and few ductular NCAM+ cells. Subsequent to injury, NCAM+ cells expand and polySia is produced by DRs/HPCs through ST8SiaIV. PolySia weakens cell-cell and cell-matrix interactions, facilitating HGF-induced migration. Differentiation of HPCs to hepatocytes in vitro results in both transcriptional down-regulation of polySia and cleavage of polySia-NCAM. Cleavage of polySia by endosialidase (endoN) during liver regeneration reduces migration of DRs into parenchyma.
PolySia modification of NCAM+ ductules weakens cell-cell and cell-matrix interactions, allowing DRs/HPCs to migrate for normal development and regeneration. Modulation of polySia levels may provide a therapeutic option in liver regeneration.
在严重的肝损伤中，含有多潜能肝祖细胞（HPC）的胆管反应（DRs）从门脉管分出。神经细胞黏附分子（NCAM）标记胆管和 DRs，但不标记成熟的肝细胞。NCAM 介导细胞与周围基质之间的相互作用；然而，其在肝脏发育和再生中的作用尚未确定。多唾液酸（polySia）是 NCAM 的一种独特的翻译后修饰物，由 ST8SiaII 和 ST8SiaIV 酶产生，并削弱 NCAM 相互作用。在胆碱缺乏蛋氨酸补充和 3,5-二乙氧基羰基-1,4-二氢-collidine 肝损伤和再生模型中，使用体内 HPC 检查了 NCAM 合成酶 ST8SiaII 和 ST8SiaIV 与 polySia 的作用，在增殖、分化和迁移模型中使用体外模型，以及使用多唾液酸转移酶基因缺陷的小鼠模型（St8sia 2+/-4+/-, 和 St8sia2-/-4-/-）。我们表明，在肝脏发育过程中，多唾液酸对于正确形成胆管是必需的，因为两种多唾液酸转移酶的基因缺陷（St8sia2+/-4+/- 和 St8sia2-/-4-/- 小鼠）导致胆管发育异常。在正常肝脏中，多唾液酸的产生很少，胆管 NCAM+细胞也很少。损伤后，NCAM+细胞扩增，DRs/HPCs 通过 ST8SiaIV 产生多唾液酸。多唾液酸削弱细胞-细胞和细胞-基质相互作用，促进 HGF 诱导的迁移。体外 HPC 向肝细胞的分化导致多唾液酸和多唾液酸-NCAM 的转录下调。内唾液酸酶（endoN）在肝再生过程中裂解多唾液酸可减少 DRs 向实质的迁移。
NCAM+胆管小管的多唾液酸修饰削弱了细胞-细胞和细胞-基质相互作用，使 DRs/HPC 能够迁移以实现正常发育和再生。多唾液酸水平的调节可能为肝脏再生提供一种治疗选择。
