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

肝脏的反复损伤导致伤口的慢性愈合，从而导致病理性瘢痕组织的形成。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，这种细胞外基质主要由肝星状细胞（hsc）分泌。在慢性损伤组织中，造血干细胞转分化为活化的肌成纤维细胞表型，不仅上调基质的产生，还上调增殖、迁移和收缩性。由于造血干细胞充当周细胞（PCs），粘附并包裹肝窦内皮细胞（LSECs），其收缩性的增加导致肝窦收缩。与此同时，LSECs被脱壳，将窦状血管转化为紧密密封的毛细血管，血液与周围组织之间的跨血管交换大大减少。总的来说，这些过程导致纤维化肝窦阻力升高。此外，由于纤维化组织的营养和氧气供应减少，血管的生长也被诱导。这些发现证明了血管生成和纤维化之间的密切关系。如果不及时治疗，纤维化发展为肝硬化，其特征是强烈的形态学改变，并伴有门脉高压和肝功能下降，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造血干细胞数量的增加，正弦稳定性提高。当壁hsc上调收缩性时，窦直径减小。这就提出了一个问题，即hsc如何附着在LSECs上并触发收缩力。我们在小鼠模型中的初步数据表明，毛细化的LSECs可扩增JAM-B的表达，而肌成纤维hsc可诱导JAM-C的产生。JAM-B和JAM-C是连接粘附分子，介导不同细胞类型如内皮细胞和白细胞之间的相互作用。因此，本研究的目的是研究JAM-B和JAM-C在纤维化肝中活化的hsc和毛细化的LSECs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由毒素四氯化碳引起的慢性肝损伤。我们的初步研究表明，造血干细胞可以以一种依赖于jam - c的方式结合可溶性JAM-B。此外，通过阻断亲同性而非亲异性的JAM-C相互作用，可以抑制HSC的收缩性。因此，JAM-B/JAM-C结合可能对HSC与LSECs的粘附很重要，而JAM-C/JAM-C结合在HSC的收缩性中起作用。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构，如窦缩窄或血管生成增加，因此可以作为抗纤维化治疗。

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.