Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear...

Area of Science:

• Cell biology
• Biophysics
• Hepatology

Background:

• Matrix rigidity influences cell behavior and increases during liver fibrosis.
• The impact of matrix stiffness on primary hepatocyte function was previously unknown.
• Liver fibrosis involves increased matrix stiffness, potentially affecting liver-specific functions.

Purpose of the Study:

• To investigate the effects of increased matrix rigidity on primary hepatocyte function.
• To determine the range of matrix stiffness in normal and fibrotic livers.
• To elucidate the molecular mechanisms by which matrix stiffness affects hepatocyte function.

Main Methods:

• Atomic force microscopy was used to measure matrix stiffness in normal and fibrotic liver lobules.
• Primary hepatocytes were cultured on collagen matrices with tunable rigidity.
• Mechanotransduction pathways, including focal adhesion kinase and Rho/Rho-associated protein kinase, were analyzed.

Main Results:

• Normal liver matrix stiffness is ~150 Pa, increasing to 1-6 kPa in fibrotic livers.
• Fibrotic matrix stiffness significantly inhibited hepatocyte-specific functions and cytoskeletal tension.
• Fibrotic matrix stiffness inhibited the hepatocyte nuclear factor 4 alpha (HNF4α) transcriptional network.
• Mechanotransduction was activated in hepatocytes on stiff matrices via focal adhesion kinase.
• Blocking the Rho/Rho-associated protein kinase pathway rescued HNF4α expression on stiff matrices.

Conclusions:

• Fibrotic matrix stiffness inhibits hepatocyte function by disrupting the HNF4α network through the Rho/Rho-associated protein kinase pathway.
• Understanding matrix rigidity's role is crucial for comprehending hepatocyte dysfunction in liver cirrhosis.
• This research may lead to novel therapeutic strategies for chronic liver disease.