Extracellular matrix rigidity has important effects on cell behaviors and is increased sharply during liver fibrosis and cirrhosis. Hepatic blood flow is essential in maintaining hepatocytes (HC) functions. However, it is still unclear how matrix stiffness and shear stresses orchestrate HC phenotype in concert. A fibrotic 3D liver sinusoidal model is constructed using a porous membrane sandwiched between two PDMS layers with respective flow channels. The HC are cultured in collagen gels of various stiffness in the lower channel, while the upper channel is pre-seeded with liver sinusoidal endothelial cells (LSEC) and accessible to shear flow. The results reveal that HC cultured within stiffer matrices exhibit less albumin production and cytochrome P450 (CYP450) reductase expression. Low shear stresses enhance synthetic and metabolic functions of HC, while high shear stresses lead to the loss of HC phenotype. Furthermore, both two mechanical factors regulate HC functions in a cooperative way by complementing with each other. These observations are likely attributed to mechanically-induced mass transport or key signaling molecule of hepatocyte nuclear factor 4 alpha (HNF4α). Present results provide an insight in understanding the mechanisms of HC dysfunction in liver fibrosis and cirrhosis especially from viewpoint of matrix stiffness and blood flow.

中文翻译：

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基质刚度和剪切应力调节纤维化肝窦模型中的肝细胞功能

细胞外基质刚性对细胞行为有重要影响，并且在肝纤维化和肝硬化期间急剧增加。肝血流对于维持肝细胞 (HC) 功能至关重要。然而，仍不清楚基质刚度和剪切应力如何协调 HC 表型。使用夹在具有各自流动通道的两个 PDMS 层之间的多孔膜构建纤维化 3D 肝正弦模型。HC 在下通道中在各种硬度的胶原凝胶中培养，而上通道预先接种了肝窦内皮细胞 (LSEC)，可用于剪切流。结果表明，在较硬的基质中培养的 HC 表现出较少的白蛋白产生和细胞色素 P450 (CYP450) 还原酶的表达。低剪切应力增强 HC 的合成和代谢功能，而高剪切应力会导致 HC 表型的丧失。此外，这两个机械因素通过相互补充以合作的方式调节HC功能。这些观察结果可能归因于机械诱导的质量传递或肝细胞核因子 4 α (HNF4α) 的关键信号分子。目前的研究结果为了解肝纤维化和肝硬化中 HC 功能障碍的机制提供了一种见解，特别是从基质硬度和血流的角度来看。