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Cellular interplay in the fibrotic liver: Adhesion molecules JAM-B and JAM-C as mediators of sinusoid/pericyte interaction.

纤维化肝脏中的细胞相互作用：粘附分子 JAM-B 和 JAM-C 作为血窦/周细胞相互作用的介质。

基本信息

批准号：
261286070
负责人：
Privatdozentin Dr. Edith Hintermann
金额：
--
依托单位：
Zentrum der Pharmakologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/261286070?language=en
关键词：
Cellular interplay fibrotic liver Adhesion

项目摘要

Repeated injury of the liver induces chronic wound healing, which leads to pathological scar tissue formation. Such fibrotic tissue is generated due to increased production of collagen-rich extracellular matrix, which is mainly secreted by hepatic stellate cells (HSCs). In the chronically damaged tissue, HSCs transdifferentiate into an activated, myofibroblastic phenotype and upregulate not only matrix production but also proliferation, migration and contractility. Since HSCs act as pericytes (PCs), adhering to and embracing liver sinusoidal endothelial cells (LSECs), an increase in their contractility leads to sinusoid constriction. In parallel, LSECs get defenestrated, transforming sinusoids into tightly sealed capillaries with a strongly reduced transvascular exchange between blood and surrounding tissue. Overall, these processes lead to a rise in sinusoidal resistance in the fibrotic liver. In addition, the growth of blood vessels is induced due to a reduced supply of fibrotic tissue with nutrients and oxygen. These findings demonstrate a close relationship between angiogenesis and fibrosis. If untreated, fibrosis progresses to cirrhosis, which is characterized by strong morphological changes combined with portal hypertension and reduced liver function, eventually leading to liver failure. During fibrogenesis sinusoidal stability raises as the increasing number of HSCs attach to the vessel walls. When mural HSCs upregulate contractility the sinusoid diameter decreases. This poses the question as to how HSCs can attach to LSECs and trigger contractile forces. Our preliminary data in mouse models have shown that capillarized LSECs amplify JAM-B expression, whereas myofibroblastic HSCs induce JAM-C production. JAM-B and JAM-C are junctional adhesion molecules which mediate the interaction between different cell types like endothelial cells and leukocytes. Therefore, it is the aim of this work to study the role of JAM-B and JAM-C during the interaction between activated HSCs and capillarized LSECs in the fibrotic liver. To this end, we will analyze two different fibrosis models: Adenovirus-induced autoimmune hepatitis and chronic liver damage by the toxin carbon tetrachloride. Our initial studies demonstrate that HSCs can bind soluble JAM-B in a JAM-C-dependent manner. Furthermore, HSC contractility can be inhibited by blocking homophilic but not heterophilic JAM-C interaction. Therefore, it is possible that JAM-B/JAM-C binding is important for HSC adhesion to LSECs, whereas JAM-C/JAM-C binding plays a role in HSC contractility. Specific blockade of JAM-B and/or JAM-C controlled processes could reduce fibrosis-associated vascular remodelling e.g. sinusoid constriction or increased angiogenesis, and could therefore act as an anti-fibrotic therapy.

肝脏的反复损伤诱导慢性伤口愈合，这导致病理性瘢痕组织形成。这种纤维化组织是由于富含胶原的细胞外基质的产生增加而产生的，所述细胞外基质主要由肝星状细胞（HSC）分泌。在慢性损伤的组织中，HSC转分化成活化的成肌纤维细胞表型，不仅上调基质产生，而且上调增殖、迁移和收缩性。由于HSC作为周细胞（PC），粘附并拥抱肝窦内皮细胞（LSEC），其收缩力的增加导致窦状隙收缩。与此同时，LSEC被排出，将窦状隙转化为紧密密封的毛细血管，血液和周围组织之间的经血管交换大大减少。总体而言，这些过程导致纤维化肝脏中的正弦阻力上升。此外，由于纤维化组织的营养物和氧气供应减少，血管的生长被诱导。这些发现证明了血管生成和纤维化之间的密切关系。如果不治疗，纤维化进展为肝硬化，其特征在于强烈的形态学变化结合门静脉高压和肝功能降低，最终导致肝功能衰竭。在纤维形成过程中，随着附着在血管壁上的HSC数量的增加，窦状隙的稳定性提高。当壁HSC上调收缩性时，窦状隙直径减小。这就提出了一个问题，即HSC如何附着在LSEC上并触发收缩力。我们在小鼠模型中的初步数据表明，毛细血管化的LSEC扩增了JAM-B的表达，而肌纤维母细胞HSC诱导了JAM-C的产生。JAM-B和JAM-C是介导不同细胞类型如内皮细胞和白细胞之间相互作用的连接粘附分子。因此，本工作的目的是研究JAM-B和JAM-C在纤维化肝脏中活化的HSC和毛细血管化的LSEC之间的相互作用中的作用。为此，我们将分析两种不同的纤维化模型：腺病毒诱导的自身免疫性肝炎和四氯化碳毒素引起的慢性肝损伤。我们的初步研究表明，HSC可以以JAM-C依赖的方式结合可溶性JAM-B。此外，HSC收缩性可以通过阻断嗜同性而非嗜异性的JAM-C相互作用来抑制。因此，可能JAM-B/JAM-C结合对于HSC粘附至LSEC是重要的，而JAM-C/JAM-C结合在HSC收缩性中起作用。特异性阻断JAM-B和/或JAM-C控制的过程可以减少纤维化相关的血管重塑，例如窦状隙收缩或增加的血管生成，因此可以用作抗纤维化疗法。