Regulators, functions, and mechanotransduction pathways of matrix stiffness in hepatic disease

Abstract

The extracellular matrix (ECM) provides physical support and imparts significant biochemical and mechanical cues to cells. Matrix stiffening is a hallmark of liver fibrosis and is associated with many hepatic diseases, especially liver cirrhosis and carcinoma. Increased matrix stiffness is not only a consequence of liver fibrosis but is also recognized as an active driver in the progression of fibrotic hepatic disease. In this article, we provide a comprehensive view of the role of matrix stiffness in the pathological progression of hepatic disease. The regulators that modulate matrix stiffness including ECM components, MMPs, and crosslinking modifications are discussed. The latest advances of the research on the matrix mechanics in regulating intercellular signaling and cell phenotype are classified, especially for hepatic stellate cells, hepatocytes, and immunocytes. The molecular mechanism that sensing and transducing mechanical signaling is highlighted. The current progress of ECM stiffness’s role in hepatic cirrhosis and liver cancer is introduced and summarized. Finally, the recent trials targeting ECM stiffness for the treatment of liver disease are detailed.

The Role of Mechanotransduction in Contact Inhibition of Locomotion and Proliferation

“…Furthermore, the involvement of other biological pathways, such as metabolism (ATP synthesis and glycolysis) and Rho signaling, in CI and mechanotransduction has been discovered [263][264][265][266][267][268]. These findings have already led to the development of novel treatment strategies for certain diseases [15,269,270]. For instance, in some cases, reducing ECM stiffness using lysyl oxidase inhibitors has improved T cell migration and enhanced the effectiveness of anti-PD-1 treatment [271].…”

“…Mechanotransduction refers to the cellular process through which cells perceive mechanical forces from their environment, as well as forces generated within the cells themselves, and convert them into biochemical and bioelectric signals and subsequent cellular responses, including cell adhesion, shape change, and migration, tissue development, cell proliferation, differentiation, and gene expression [10][11][12]. This intricate process enables cells to sense and adapt to various mechanical cues, such as shear stress, tension, compression, substrate stiffness, and even gravitational forces [13][14][15][16]. Mechanotransduction is attracting attention as a new target for disease treatment and tissue engineering [17][18][19].…”

Contact Inhibition and Mechanotransduction

“…Furthermore, the involvement of other biological pathways, such as metabolism (ATP synthesis and glycolysis) and Rho signaling, in CI and mechanotransduction has been discovered [250][251][252][253][254][255]. These findings have already led to the development of novel treatment strategies for certain diseases [14,256,257]. For instance, in some cases, reducing ECM stiffness using lysyl oxidase inhibitor has improved T cell migration and enhanced the effectiveness of anti-PD-1 [258].…”

“…Mechanotransduction refers to the cellular process through which cells perceive mechanical forces from their environment, as well as forces generated within the cells themselves, and convert them into biochemical and bioelectric signals and subsequent cellular responses including cell adhesion, shape change, and migration, tissue development, cell proliferation, differentiation, and gene expression [9][10][11]. This intricate process enables cells to sense and adapt to various mechanical cues, such as shear stress, tension, compression, substrate stiffness, and even gravitational forces [12][13][14][15]. Mechanotransduction is attracting attention as a new target for disease treatment and tissue engineering [16][17][18].…”

“…The following supporting information can be downloaded at: www.mdpi.com/xxx/ s1, Table S1 and Table S2 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17].…”