Li Yuchang, Lua Ingrid, French Samuel W, Asahina Kinji
Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; and.
Department of Pathology, Harbor-UCLA Medical Center, Torrance, California.
Am J Physiol Gastrointest Liver Physiol. 2016 Feb 15;310(4):G262-72. doi: 10.1152/ajpgi.00257.2015. Epub 2015 Dec 23.
Mesothelial cells (MCs) form a single layer of the mesothelium and cover the liver surface. A previous study demonstrated that, upon liver injury, MCs migrate inward from the liver surface and give rise to hepatic stellate cells (HSCs) in biliary fibrosis induced by bile duct ligation (BDL) or myofibroblasts in CCl4-induced fibrosis. The present study analyzed the role of transforming growth factor-β (TGF-β) signaling in mesothelial-mesenchymal transition (MMT) and the fate of MCs during liver fibrosis and its regression. Deletion of TGF-β type II receptor (Tgfbr2) gene in cultured MCs suppressed TGF-β-mediated myofibroblastic conversion. Conditional deletion of Tgfbr2 gene in MCs reduced the differentiation of MCs to HSCs and myofibroblasts in the BDL and CCl4 models, respectively, indicating that the direct TGF-β signaling in MCs is responsible to MMT. After BDL and CCl4 treatment, MC-derived HSCs and myofibroblasts were distributed near the liver surface and the thickness of collagen was increased in Glisson's capsule beneath the liver surface. Fluorescence-activated cell sorting analysis revealed that MC-derived HSCs and myofibroblasts store little vitamin A lipids and have fibrogenic phenotype in the fibrotic livers. MCs contributed to 1.4 and 2.0% of activated HSCs in the BDL and CCl4 models, respectively. During regression of CCl4-induced fibrosis, 20% of MC-derived myofibroblasts survived in the liver and deactivated to vitamin A-poor HSCs. Our data indicate that MCs participate in capsular fibrosis by supplying vitamin A-poor HSCs during a process of liver fibrosis and regression.
间皮细胞（MCs）构成间皮的单层结构并覆盖肝脏表面。先前的一项研究表明，在肝损伤时，MCs从肝脏表面向内迁移，并在胆管结扎（BDL）诱导的胆汁性纤维化中产生肝星状细胞（HSCs），或在四氯化碳诱导的纤维化中产生肌成纤维细胞。本研究分析了转化生长因子-β（TGF-β）信号在间皮-间充质转化（MMT）中的作用以及肝纤维化及其消退过程中MCs的命运。在培养的MCs中删除TGF-β II型受体（Tgfbr2）基因可抑制TGF-β介导的肌成纤维细胞转化。在BDL和四氯化碳模型中，MCs中Tgfbr2基因的条件性缺失分别减少了MCs向HSCs和肌成纤维细胞的分化，表明MCs中的直接TGF-β信号负责MMT。在BDL和四氯化碳处理后，MCs来源的HSCs和肌成纤维细胞分布在肝脏表面附近，肝脏表面下方的Glisson囊内胶原厚度增加。荧光激活细胞分选分析显示，MCs来源的HSCs和肌成纤维细胞在纤维化肝脏中储存的维生素A脂质很少且具有促纤维化表型。在BDL和四氯化碳模型中，MCs分别占活化HSCs的1.4%和2.0%。在四氯化碳诱导的纤维化消退过程中，20%的MCs来源的肌成纤维细胞在肝脏中存活并失活为维生素A缺乏的HSCs。我们的数据表明，MCs在肝纤维化和消退过程中通过提供维生素A缺乏的HSCs参与包膜纤维化。
