Center for Biomechanics and Bioengineering, Institute of Mechanics, Chinese Academy of Sciences, Beijing, People's Republic of China.
Key Laboratory of Microgravity (National Microgravity Laboratory), Institute of Mechanics, Chinese Academy of Sciences, Beijing, People's Republic of China.
Am J Physiol Gastrointest Liver Physiol. 2021 Mar 1;320(3):G272-G282. doi: 10.1152/ajpgi.00379.2019. Epub 2020 Dec 9.
Extracellular matrix (ECM) rigidity has important effects on cell behaviors and increases sharply in liver fibrosis and cirrhosis. Hepatic blood flow is essential in maintaining hepatocytes' (HCs) functions. However, it is still unclear how matrix stiffness and shear stresses orchestrate HC phenotype in concert. A fibrotic three-dimensional (3-D) liver sinusoidal model is constructed using a porous membrane sandwiched between two polydimethylsiloxane (PDMS) layers with respective flow channels. The HCs are cultured in collagen gels of various stiffnesses in the lower channel, whereas the upper channel is pre-seeded with liver sinusoidal endothelial cells (LSECs) and accessible to shear flow. The results reveal that HCs cultured within stiffer matrices exhibit reduced albumin production and cytochrome 450 (CYP450) reductase expression. Low shear stresses enhance synthetic and metabolic functions of HC, whereas high shear stresses lead to the loss of HC phenotype. Furthermore, both mechanical factors regulate HC functions by complementing each other. These observations are likely attributed to mechanically induced mass transport or key signaling molecule of hepatocyte nuclear factor 4α (HNF4α). The present study results provide an insight into understanding the mechanisms of HC dysfunction in liver fibrosis and cirrhosis, especially from the viewpoint of matrix stiffness and blood flow. A fibrotic three-dimensional (3-D) liver sinusoidal model was constructed to mimic different stages of liver fibrosis in vivo and to explore the cooperative effects of matrix stiffness and shear stresses on hepatocyte (HC) functions. Mechanically induced alterations of mass transport mainly contributed to HC functions via typical mechanosensitive signaling.
细胞外基质（ECM）硬度对细胞行为有重要影响，并在肝纤维化和肝硬化中急剧增加。肝血流对于维持肝细胞（HCs）的功能至关重要。然而，基质硬度和切应力如何协同调节 HC 表型仍不清楚。使用夹在两层聚二甲基硅氧烷（PDMS）层之间的多孔膜构建了一个纤维化的三维（3-D）肝窦模型，其中各自具有流道。将 HCs 在下部通道的不同硬度的胶原凝胶中培养，而上部通道预先接种有肝窦内皮细胞（LSECs）并可承受切变流。结果表明，在较硬基质中培养的 HCs 表现出白蛋白产生和细胞色素 450（CYP450）还原酶表达减少。低切应力增强 HC 的合成和代谢功能，而高切应力导致 HC 表型丧失。此外，两种机械因素通过相互补充来调节 HC 的功能。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 4α（HNF4α）的关键信号分子。本研究结果为理解肝纤维化和肝硬化中 HC 功能障碍的机制提供了深入了解，特别是从基质硬度和血流的角度。构建了一个纤维化的三维（3-D）肝窦模型，以模拟体内不同阶段的肝纤维化，并探讨基质硬度和切应力对肝细胞（HC）功能的协同作用。质量传递的机械诱导改变主要通过典型的机械敏感信号来影响 HC 功能。
