Fibrinogen improves liver function via promoting cell aggregation and fibronectin assembly in hepatic spheroids
Fibrinogen improves liver function via promoting cell aggregation and fibronectin assembly in hepatic spheroids
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纤维蛋白原通过促进肝球体中的细胞聚集和纤连蛋白组装来改善肝功能
DOI：
10.1016/j.biomaterials.2021.121266
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发表时间：
2021-12-04
期刊：
影响因子：
14
通讯作者：
Wang, Yunfang
中科院分区：
文献类型：
--
作者：
Li, Ruihong;Liu, Juan;Wang, Yunfang
肝脏的许多关键功能依赖于实质细胞与由邻近细胞和细胞外基质组成的微环境之间的相互作用。基质中的生物大分子是动态变化的，通过与细胞表面受体、抗原、离子通道等相互作用参与各种生理过程。我们发现，成年大鼠制备的大鼠肝脏生物基质支架（LBS）比新生大鼠或老年大鼠制备的大鼠肝脏生物基质支架（LBS）更能增强肝球体的功能。结合基质体和生物信息学分析，我们进一步发现糖蛋白、纤维连接蛋白和纤维蛋白原可能具有改善肝细胞功能的特殊潜力。在培养体系中加入纤维连接蛋白和纤维蛋白原后，人原代肝细胞类器官和HepaRG球体表现出更成熟的肝细胞表型。在肝球体培养过程中，纤维蛋白原通过促进细胞聚集，帮助纤维连接蛋白在细胞表面聚集，导致细胞间连接增加，从而激活Wnt/ β -catenin通路。纤维连接素-整合素α V β 1-Wnt/ β -连环蛋白可能是实质细胞微环境信号转导的轴。重要的是，纤维蛋白原增强了信号转导。这些结果表明，在三维培养体系中加入纤维连接蛋白和纤维蛋白原是一种诱导实质细胞功能成熟的新策略。
Many key functions performed by the liver depend on the interaction between parenchymal cells and the microenvironment comprised of neighboring cells and extracellular matrix. The biological macromolecules in the matrix, which are dynamically changing, participate in various physiological processes through interactions with cell surface receptors, antigens, and ion channels. We found the rat liver biomatrix scaffold (LBS) prepared from adult rats is more effective in enhancing the function of hepatic spheroids than those derived from newborn or senile rats. Combined with matrisome and bioinformatics analyses, we further found that the glycoproteins, fibronectin and fibrinogen may have special potential for improving hepatocyte function. Human primary hepatocyte organoids and HepaRG spheroids showed more mature hepatocyte phenotype after adding fibronectin and fibrinogen to the culture system. During the cultivation of hepatic spheroids, fibrinogen resulted in an increase in cell-cell junction by promoting cell aggregation and helping fibronectin to assemble on cell surface, which resulted in activation of Wnt/beta-catenin pathway. Fibronectin-integrin alpha V beta 1-Wnt/beta-catenin may be the axis of signal transduction in parenchymal cell microenvironment. Importantly, fibrinogen enhances the signal transduction. These results suggest that the addition of fibronectin and fibrinogen to the 3D culture system is a new strategy for inducing parenchymal cell functional maturation.