Microfibrous Extracellular Matrix Changes the Liver Hepatocyte Energy Metabolism via Integrins

Cell line-based liver models are critical tools for liver-related studies. However, the conventional monolayer culture of hepatocytes, the most widely used in vitro model, does not have the extracellular matrix (ECM), which contributes to the three-dimensional (3D) arrangement of the hepatocytes in the liver. As a result, the metabolic properties of the hepatocytes in the monolayer tissue culture may not accurately reflect those of the hepatocytes in the liver. Here, we developed a modular platform for 3D hepatocyte cultures on fibrous ECMs produced by electrospinning, a technique that can turn a polymer solution to the micro/nanofibers and has been widely used to produce scaffolds for 3D cell cultures. Metabolomics quantitation by liquid chromatography-mass spectrometry (LC-MS) indicated that Huh7 hepatocytes grown in microfibers electrospun from silk fibroin exhibited reduced glycolysis and tricarboxylic acid (TCA) cycle, as compared to the cells cultured as a monolayer. Further mechanistic studies suggested that integrins were correlated to the ECM's effects. This is the first time to report how an ECM scaffold could affect the fundamental metabolism of the hepatocytes via integrins.