Klaas Mariliis, Kangur Triin, Viil Janeli, Mäemets-Allas Kristina, Minajeva Ave, Vadi Krista, Antsov Mikk, Lapidus Natalia, Järvekülg Martin, Jaks Viljar
Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Estonia.
Laboratory of Physics of Nano Structures, Institute of Physics, University of Tartu, Estonia.
Sci Rep. 2016 Jun 6;6:27398. doi: 10.1038/srep27398.
While the cellular mechanisms of liver regeneration have been thoroughly studied, the role of extracellular matrix (ECM) in liver regeneration is still poorly understood. We utilized a proteomics-based approach to identify the shifts in ECM composition after CCl4 or DDC treatment and studied their effect on the proliferation of liver cells by combining biophysical and cell culture methods. We identified notable alterations in the ECM structural components (eg collagens I, IV, V, fibronectin, elastin) as well as in non-structural proteins (eg olfactomedin-4, thrombospondin-4, armadillo repeat-containing x-linked protein 2 (Armcx2)). Comparable alterations in ECM composition were seen in damaged human livers. The increase in collagen content and decrease in elastic fibers resulted in rearrangement and increased stiffness of damaged liver ECM. Interestingly, the alterations in ECM components were nonhomogenous and differed between periportal and pericentral areas and thus our experiments demonstrated the differential ability of selected ECM components to regulate the proliferation of hepatocytes and biliary cells. We define for the first time the alterations in the ECM composition of livers recovering from damage and present functional evidence for a coordinated ECM remodelling that ensures an efficient restoration of liver tissue.
虽然肝脏再生的细胞机制已得到深入研究，但细胞外基质（ECM）在肝脏再生中的作用仍知之甚少。我们采用基于蛋白质组学的方法来确定四氯化碳（CCl4）或二甲基二硫代氨基甲酸钠（DDC）处理后ECM组成的变化，并通过结合生物物理和细胞培养方法研究其对肝细胞增殖的影响。我们发现ECM结构成分（如I型、IV型、V型胶原蛋白、纤连蛋白、弹性蛋白）以及非结构蛋白（如嗅觉介质-4、血小板反应蛋白-4、含犰狳重复序列的X连锁蛋白2（Armcx2））有显著改变。在受损的人类肝脏中也观察到了类似的ECM组成变化。胶原蛋白含量的增加和弹性纤维的减少导致受损肝脏ECM的重新排列和硬度增加。有趣的是，ECM成分的改变是不均匀的，在汇管区和中央静脉周围区域有所不同，因此我们的实验证明了所选ECM成分调节肝细胞和胆管细胞增殖的不同能力。我们首次定义了受损肝脏恢复过程中ECM组成的变化，并提供了功能性证据，证明存在协调的ECM重塑，以确保肝组织的有效恢复。
