Role of matrix rigidity on hepatocytes and liver sinusoidal endothelial cells in hepatic fibrogenesis

Liver fibrosis, which results from chronic liver damage in conjunction with the accumulation of extracellular matrix (ECM) proteins, is characteristic of several chronic liver diseases. As the liver becomes fibrotic, a cascade... [ view full abstract ]

Liver fibrosis, which results from chronic liver damage in conjunction with the accumulation of extracellular matrix (ECM) proteins, is characteristic of several chronic liver diseases. As the liver becomes fibrotic, a cascade of events occurs including activation of hepatic stellate cells that trigger the release of chemokines and inflammatory stimulants, and extensive remodeling of the extracellular matrix that leads to liver stiffening. Numerous studies demonstrate that an increase in stiffness not only correlates with fibrosis, it also contributes to its progression. An important remaining insight is to understand the role of matrix stiffness as related to subtle but pivotal changes in cell physiology. Our study focuses on the extent to which matrix stiffness uniquely regulates the cellular function of hepatocytes and liver sinusoidal endothelial cells (LSECs). We have demonstrated, using mechanically tunable substrate, that fibrotic levels of matrix stiffness significantly decreased hepatocyte-specific functions; downregulated key drug transporter genes, and downregulated epithelial cell phenotype markers. Additionally, we have demonstrated that LSECs cultured on different levels of stiffness result in rapid loss in fenestrae and hyaluronic acid endocytosis that mimics the fibrosis response observed in vivo. These data suggest that increased stiffness as an isolated variable, is sufficient to modulate hepatocyte and LSEC function, and drive the progression of liver fibrosis. This study blends liver biology, mechanobiology, and materials design to develop quantitative and mechanistic insights into the impact of liver stiffening in fibrosis, with implications in understanding of liver fibrosis and the future development of new therapeutic strategies for liver fibrosis.