Murine junctional adhesion molecules JAM-B and JAM-C mediate endothelial and stellate cell interactions during hepatic fibrosis
Murine junctional adhesion molecules JAM-B and JAM-C mediate endothelial and stellate cell interactions during hepatic fibrosis
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DOI：
10.1080/19336918.2016.1178448
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发表时间：
2016-01-01
影响因子：
3.2
通讯作者：
Christen, Urs
中科院分区：
文献类型：
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作者：
Hintermann, Edith;Bayer, Monika;Christen, Urs
经典的连接粘附分子JAM-A、JAM-B和JAM-C影响血管通透性、细胞极性以及白细胞募集和迁移到发炎组织中。随着血管系统在慢性损伤、纤维化肝脏中重塑，我们旨在确定连接粘附分子在这一病理过程中的分布和作用。因此，通过免疫组织化学分析幼稚或四氯化碳处理的小鼠的肝脏，以定位所有3种经典的连接粘附分子。分离肝星状细胞和内皮细胞，并进行免疫细胞化学和流式细胞术，以确定JAM-B和JAM-C的定位和功能。细胞进一步用于进行收缩和迁移测定，并研究肝星状细胞的内皮小管形成和细胞周覆盖。我们发现，在健康组织中，JAM-A普遍表达，而JAM-B和JAM-C仅限于血管。在纤维化过程中，JAM-B和JAM-C水平在内皮细胞中增加，并且JAM-C在肌纤维母细胞肝星状细胞中重新产生。可溶性JAM-C阻断肝星状细胞的收缩性，但增加运动性。此外，可溶性JAM-C减少了内皮微管形成和内皮细胞/星状细胞相互作用。因此，在肝纤维化过程中，血管内皮上的JAM-B和JAM-C表达增加。更重要的是，JAM-C出现在肌纤维母细胞肝星状细胞上，将它们作为周细胞连接到JAM-B阳性内皮细胞。这种JAM-B/JAM-C介导的内皮细胞和星状细胞之间的相互作用稳定了血管壁，并可控制正弦直径。JAM-C/JAM-C相互作用介导的肝星状细胞收缩增加可能导致肝内血管收缩，这是肝硬化的主要并发症。
Classical junctional adhesion molecules JAM-A, JAM-B and JAM-C influence vascular permeability, cell polarity as well as leukocyte recruitment and immigration into inflamed tissue. As the vasculature becomes remodelled in chronically injured, fibrotic livers we aimed to determine distribution and role of junctional adhesion molecules during this pathological process. Therefore, livers of naive or carbon tetrachloride-treated mice were analyzed by immunohistochemistry to localize all 3 classical junctional adhesion molecules. Hepatic stellate cells and endothelial cells were isolated and subjected to immunocytochemistry and flow cytometry to determine localization and functionality of JAM-B and JAM-C. Cells were further used to perform contractility and migration assays and to study endothelial tubulogenesis and pericytic coverage by hepatic stellate cells. We found that in healthy tissue, JAM-A was ubiquitously expressed whereas JAM-B and JAM-C were restricted to the vasculature. During fibrosis, JAM-B and JAM-C levels increased in endothelial cells and JAM-C was de novo generated in myofibroblastic hepatic stellate cells. Soluble JAM-C blocked contractility but increased motility in hepatic stellate cells. Furthermore, soluble JAM-C reduced endothelial tubulogenesis and endothelial cell/stellate cell interaction. Thus, during liver fibrogenesis, JAM-B and JAM-C expression increase on the vascular endothelium. More importantly, JAM-C appears on myofibroblastic hepatic stellate cells linking them as pericytes to JAM-B positive endothelial cells. This JAM-B/JAM-C mediated interaction between endothelial cells and stellate cells stabilizes vessel walls and may control the sinusoidal diameter. Increased hepatic stellate cell contraction mediated by JAM-C/JAM-C interaction may cause intrahepatic vasoconstriction, which is a major complication in liver cirrhosis.