Introduction to the molecular basis of liver stiffness and its relation to mechano-signaling

Abstract

This chapter introduces to the book part “Molecular Basis of Liver Stiffness and Cell Biology.” The molecular basis of liver stiffness (LS) is complex and multifactorially controlled at the systemic, cellular, and intracellular level. In addition, all cells including liver cells sense and respond to their environmental stiffness through mechano-signaling processes. Principally, stiffness is modulated either by structural conditions, e.g., matrix deposition such as collagen, the degree of perfusion or pressure-related conditions that are all inter-related. Pressure itself is controlled in a complex manner. While the static component of pressure is mainly affected by the vascular bed with its elastic properties and water filling status, the dynamic component is related to blood flow, hepatic resistance, and the hemorheology. At the intracellular level, stiffness is affected by intracellular pressure and stretch forces on the cellular membranes and intermediary filaments. The intracellular pressure is likewise controlled by many conditions including transport proteins to control osmotic pressure, or water influx, e.g., by aquaporins. We are still at the beginning to understand how liver cells, fibroblasts and hepatic stellate cells sense environmental stiffness. Quantitative in vitro studies of cells adhering to gels of varying adjustable stiffness are a useful tool in order to elucidate these mechanisms. Other chapters of this book part will introduce to the role of stiffness for hepatocyte function in vitro, to liver mechanics and the profibrotic response at the cellular level and, finally, to the role of sinusoidal pressure and hepatic arterialization in driving hepatic fibrosis. It is expected that biomechanic concepts will be instrumental for our future understanding of stiffness, fibrosis development and liver diseases.